c.) infected with L. amazonensis or L. braziliensis stationary promastigotes (2 × 106 in PBS) in the right hind foot. At indicated time of infection, we collected popliteal draining LN cells and splenocytes from individual OSI-906 order mice. To ensure sufficient cells for staining and subsequent analyses, we conveniently pooled draining LN cells within the group into two sample sets, such as three draining LNs into one set and the other two draining LNs into the other set. Cells were then stimulated with a PMA/ionomycin/Golgi Plug (BD Biosciences) for 6 h. Cells were first stained for surface markers, including CD3, CD4 and individual TCR Vβ. Then,

the intracellular IFN-γ production was stained following cytofixation/permeabilization with a Cytofix/Cytoperm Kit (BD Biosciences). The percentages of CD4+ TCR Vβ+ cells gated on CD3+ cells and TCR Vβ+ IFN-γ+ cells gated on CD4+ cells were analysed on the FACScan (BD Biosciences), and results were analysed using FlowJo software (TreeStar, Ashland, OR, USA). To obtain the absolute cell number of CD4+Vβ+ cells, we first got an averaged cell number per draining LN from each sample set. We then calculated the absolute cell number of CD3+ CD4+ TCR Vβ+ cells by multiplying the averaged absolute cell number per LN by their corresponding percentages of positively stained cells (CD3, CD4 and the individual

TCR Vβ in CD4 cells). For TCR Vβ analysis of lesion-derived cells, foot lesional tissues were collected and pooled as mentioned earlier and digested in the complete Iscove’s modified Dulbecco’s medium containing 10% FBS, 1 mm sodium pyruvate, 50 μm GSI-IX datasheet 2-ME, 50 μg/mL gentamicin and 100 U/mL penicillin, as well as collagenase/dispase (100 μg/mL) and DNase I (100 U/mL; Roche), for 2 h at 37°C. After passage through the cell strainer (40 μm; BD Biosciences), the single-cell suspension was on the top of 40% and 70% Percoll solution (Sigma). After centrifugation for 25 min at room temperature,

the purified Interleukin-3 receptor cells from a 40/70% layer of Percoll were collected and stained with CD3, CD4 and TCR Vβ Abs. The percentages of TCR Vβ+ cells gated on CD3+ CD4+ cells were analysed by FACS. B6 mice were infected with 2 × 106La or Lb promastigotes for 4 weeks. Draining LN cells were restimulated with the corresponding La or Lb antigens for 3 day, and CD4+ T cells were purified via positive selection. Naïve CD4+ T cells were used as controls. TCR Vβ repertoire clonality for purified CD4+ T cells was analysed by RT-PCR and gel-based assays using specially designed SuperTCRExpress™ kits by scientists in BioMed Immunotech Incorporation (Tampa, FL, USA). Leishmania braziliensis stationary promastigotes (2 × 106) were injected subcutaneously (s.c.) in the right hind foot. After the healing of lesions at 8 or 24 weeks, some of the mice were injected with stationary promastigotes of La (2 × 106) in the left hind foot. Naïve mice were similarly infected and used as controls.

Along with expanding molecular

explanations for brain diseases, parallel and independent hypotheses based on morphological observations are particularly useful and necessary for reasonable understanding of the brain and its dysfunction. For example, with classical methods such as silver impregnations, it is possible to differentiate underlying molecular pathologies (three-repeat tau/Campbell-Switzer vs. four-repeat tau/Gallyas silver impregnation) for improved histological diagnosis. Innovations with 3D reconstruction not only provide more realistic reproduction of the targets but also allow quantitative measurement on a 3D basis (3D volumetry). Contrary to the prevailing impression that pathological deposits are generally toxic to cells, quantification demonstrated possible countertoxic potentials of ubiquitin-positive Enzalutamide research buy intranuclear inclusions in CAG-repeat disorders on a two-dimensional basis and of glial cytoplasmic inclusions of multiple system atrophy on 3D volumetry. Furthermore, 3D extension of neurites around target lesions is now traceable in relation to the relevant clinical consequences. This neurite neuropathology may pave the way for early specific

diagnosis of neurodegenerative disorders, as established through 123I-metaiodobenzylguanidine cardiac scintigraphy for Parkinson disease, aiming at therapeutic intervention before depletion of mother neurons is feasible. For appropriate translation of sequence Sotrastaurin cost biology into the frame of human neuropathology, it is necessary to expand further the morphological dimensions so that comprehensive understanding of these disorders leads to specific diagnosis and treatment as early as possible. “
“Alzheimer’s disease (AD) is a progressive, neurodegenerative

disease, characterized by excessive accumulation of amyloid-beta (Aβ) and activation of microglia cells and astrocytes. In this research, we evaluated whether gastrodin, an active component isolated from the rhizome of Gastrodia elata, has neuroprotective effects in a mouse model of AD, Tg2576 mice. Treatment of gastrodin (60 mg/kg for 15 days) significantly improved memory impairments in the Morris water maze test and probe test. Fluorometholone Acetate Moreover, immunohistochemical and ELISA results indicated that gastrodin significantly attenuated Aβ deposition and glial activation in brains of these transgenic mice. These findings suggested that gastrodin exerted neuroprotective activity via anti-inflammatory and anti-amyloidogenic effects and that gastrodin may be a potential option for AD therapy. “
“The relationship between DJ-1 and β-catenin, and its impact on the prognosis for glioma patients has not been fully understood. This study determined the effect of DJ-1 on β-catenin and the prognostic significance of this interaction in glioma patients.

A number of phenotypic similarities between JNK1−/− T cells and Tat-POSH-treated cells were also observed. Tat-POSH-treated T cells have defective CD25 expression and cell cycle entry. They make negligible amounts of IL-2 and showed no changes in granzyme B, in stark contrast to JNK2−/− CD8+ T cells [16, 17, 19]. The effector cytokine expression profile also more closely resembles JNK1−/− than JNK2−/− T cells [13, 16, 17,

44]. Interestingly, the disruption of the POSH/JIP-1 complex for the first 48 h of activation led to a defect in the program of differentiation that resulted in a persistent deficiency in the Nivolumab cost effector response even after the ability to disrupt the complex is lost. Remarkably, T cells activated in the presence of the inhibitor for only 2 days maintained their defect throughout an antitumor immune response in vivo. Furthermore, addition of the inhibitor 2 days poststimulation had no effect. Thus, the POSH-dependent commitment to IFN-γ is programed in the first 48 h. This suggests a role (direct or indirect) for the POSH/JIP-1 network in the transcriptional regulation of epigenetic modifications necessary for the early development of T-cell effector functions. Confirmation of Tyrosine Kinase Inhibitor Library cost the programing defect

was evident from the decrease in the phosphorylation of c-Jun, defects in the induction of T-bet, Eomes, and reduced effector cytokine production. JNK1 induces the phosphorylation of c-Jun and leads to increases in the mRNA expression Celecoxib of both

T-bet and Eomes [18, 42]. Conversely, JNK2 is a negative regulator of T-bet and Eomes mRNA expression [19]. Along these lines, the protein levels of Eomes were not induced above background in the presence of Tat-POSH. Intriguingly, protein expression of T-bet in CD8+ T cells was low early but recovered at later time points. Whether this is due to changes in the POSH/JIP-1 complex or other cause is not known. These data differ slightly from previous work where JNK1 deficiency had a greater impact on T-bet than Eomes [19]. Surprisingly, Perforin expression, which is defective in JNK1−/− CD8+ T cells [18], was only slightly affected by disruption of POSH/JIP-1 complex. This was also unexpected, as Eomes deficiency has been linked to the reduction of perforin mRNA expression [42]. The differences between these and earlier works may be attributed to the methods of quantification (mRNA versus protein) and relative stability of these two proteins. Alternatively, they suggest a role for JNK in expression of these effector molecules and transcription factors that does not involve the formation of the POSH/JIP-1 complex. Interestingly, the ability to disrupt the complex with Tat-POSH diminishes over time. This indicates that the composition or configuration of the POSH/JIP1 complex changes over the course of the immune response.

The immune system can therefore represent a powerful engine of parasite evolution, with the direction of

such evolutionary trajectory depending on, among other factors, (i) the type of mechanism involved (resistance or tolerance) and (ii) the damage induced by overreacting immune defences. In this article, I will discuss these different issues focusing on selected examples of recent work conducted on two bird pathogens, the protozoa responsible Selleckchem Tanespimycin for avian malaria (Plasmodium sp.) and the bacterium Mycoplasma gallisepticum. In spite of the complexity of the vertebrate immune system, pathogens remain a pervasive threat for their hosts. The reason for this is that pathogens also respond to the threat imposed by the immune system by adopting Selleck Dorsomorphin a series of strategies that aim at escaping/reducing the effectiveness of the immune response [1]. This can lead to a co-evolutionary arms race, where the two partners are continuously selected to avoid the cost of infection and the cost of immune clearance. An additional layer of intricacy is brought by the observation that hosts can adopt different ‘strategies’ to cope with an infectious menace. Hosts can resist the

infection when immune defences keep parasite multiplication at bay and eventually clear the infection. However, hosts can also tolerate the infection. Tolerance refers to the capacity of hosts to bear the infection paying little or no fitness cost [2]. The concept of tolerance was first discussed in the plant-herbivore literature and referred to the capacity of plants to remain productive in the face of herbivores and other pests [3]. Only in recent years, the

concept has been applied to animal host–pathogen interactions [2, 4, 5]. Råberg and co-workers [2] described tolerance as the reaction norm of fitness (or health) over a range of parasite intensities (Figure 1). A flat slope relating fitness (health) to parasite burden would thus indicate a good tolerance to the infection. As such, tolerance is defined as a trait that can only be measured on groups of individuals (genotypes, Resveratrol clones, experimental groups, populations, species, etc.). Mechanisms of tolerance are diverse, and a few recent review papers have extensively discussed the different pathways leading to tolerance [6, 7]. Broadly speaking, tolerance can arise because hosts can minimize the direct damage induced by pathogens or the damage induced by an overreacting immune response. In addition to this, capacity to tissue repair and intrinsic tissue susceptibility are other essential components of tolerance. Making the distinction between tolerance and resistance has important consequences for our understanding of host strategies to face infectious diseases and parasite evolution [8]. As mentioned above, however, animal ecologists have only recently fully appreciated the need to tease apart the different strategies that hosts can adopt to reduce the cost of infection.

We thank Dr Tânia C. Felizardo

for the donation of anti-mouse IFN-γ mAb (hybridoma XMG 1.2). The authors gratefully acknowledge Dr. Telma M.T. Zorn and Dr. Sebastian A. San-Martin see more (Department of Cell and Developmental Biology, Institute of Biomedical Sciences – University of São Paulo, Brazil) for helping with the immunohistochemical reactions. “
“γ-chain (γc) cytokine receptor signaling is required for the development of all lymphocytes. Why γc signaling plays such an essential role is not fully understood, but induction of the serine/threonine kinase Pim1 is considered a major downstream event of γc as Pim1 prevents apoptosis and increases metabolic activity. Consequently, we asked whether Pim1 overexpression would suffice to restore lymphocyte development in γc-deficient mice. By analyzing Pim1-transgenic γc-deficient mice (Pim1TgγcKO), we show that Pim1 promoted T-cell development and survival in the absence of γc. Interestingly, such effects were largely limited to CD4+ lineage αβ T cells as CD4+ T-cell numbers

improved to near normal levels but CD8+ T cells remained severely lymphopenic. Notably, Pim1 over-expression failed to promote development and survival of any T-lineage cells other than αβ T cells, as we observed complete lack of γδ, NKT, FoxP3+ T regulatory cells and TCR-β+ CD8αα IELs in Pim1TgγcKO selleck products mice. Collectively, these results uncover distinct requirements for γc signaling between CD4+ αβ T cells and all other T-lineage cells, and they

identify Pim1 as a novel effector molecule U0126 research buy sufficient to drive CD4+ αβ T-cell development and survival in the absence of γc cytokine receptor signaling. All T-lineage lymphocytes depend on two nonredundant signals for their development and differentiation in the thymus. One signal is mediated by the T-cell antigen receptor (TCR) that induces thymocyte differentiation [1, 2], the other signal is mediated by cytokines of the common γ-chain (γc) cytokine family that is proposed to be essential for cell survival [3]. In the absence of either one of these signals, T-cell development in the thymus is critically impaired [4-7]. The developmental requirements for TCR signals are rather well defined. TCR signals terminate expression of recombination activating genes (RAG) and fix the specificity of the TCR [8]. TCR signals also upregulate expression of the TCR itself and induce expression of antiapoptotic molecules and cytokine receptors [8, 9]. In contrast, the role of γc signaling remains less understood. γc signals are primarily considered as survival factors, but recent data also suggested new roles for γc beyond its prosurvival function.

These layers were then infected with diluted IAV preparations for 45 min CHIR-99021 clinical trial at 37 °C in PBS and tested for presence of IAV infected cells after 7 h using a monoclonal antibody directed against the influenza A viral nucleoprotein (provided by Dr. Nancy Cox, CDC, Atlanta, GA, USA) as previously described [8, 15]. IAV was pre-incubated for 30 min at 37 °C with collectins or control buffer, followed by addition of these viral samples to the MDCK cells. Where indicated, collectins were first incubated with mAb prior to adding them to IAV. In addition to MBL, three

serum collectins have been identified in bovidae: conglutinin, CL-43 and CL-46. We have previously reported that hSP-D-NCRD has minimal binding to IAV. Using identically prepared trimeric NCRD fusion proteins, which have S-protein binding sites on the N-terminal tags, we were able to directly compare binding activity Alvelestat nmr of the NCRD of conglutinin and CL-43 to IAV. Both

of these bovine collectin NCRD bound significantly more strongly to IAV than hSP-D-NCRD, with the strongest binding obtained with CL-43 (Fig. 1A). We next compared neutralizing activity of NCRD using each at a concentration of 20 μg/ml (Fig. 1B). Results obtained on viral neutralization assays were generally consistent with the binding results. As we have previously shown, the hSP-D-NCRD lacks neutralizing activity at this concentration; however, NCRD of conglutinin and CL-43

had strong activity. Again, CL-43 had significantly stronger activity than conglutinin. We also tested a preparation of the NCRD of CL-46 that was generated in Pichia pistoris as previously described [23]. Because this preparation lacks a fusion tag, we could not directly compare binding affinity to IAV; however, the NCRD of CL-46 also had substantial neutralizing activity (Fig. 1C). In addition, the CL-46 NCRD inhibited HA activity of various strains of IAV (Table 1). As for SP-D and CL-43, the activity was dependent on glycosylation of the viral strain and the presence Nintedanib (BIBF 1120) of calcium. The Braz7/BS and Phil82/BS strains were derived from the wild-type parental strains by Dr. E. Margot Anders through growth in the presence of bovine serum β inhibitors (subsequently shown to be principally conglutinin) [18, 27]. These strains differ from the parental strains in lacking a single high mannose oligosaccharide positioned close to the sialic acid binding site of the HA, and they are partially or fully resistant to inhibition by SP-D, MBL, conglutinin and CL-43. The PR-8 strain lacks all high mannose attachments on its envelope proteins and was highly resistant to CL-46. Amino acid residues 325 and 343 define ridges on either side of the primary calcium coordination (lectin) site of SP-D (Fig. 2). These residues have a major impact on binding properties of SP-D [20, 28, 29].

Consequently, upon migrating into the intestinal lymph nodes, CD103+ DCs produce RA, which in turn drives the expression of gut-specific homing receptors (CCR9 and α4β7) by activated T and B cells [16, 17]. However, while RA is now well accepted to condition DCs within the intestine, its contribution to DC development elsewhere in the body is not yet fully resolved. Given this association with intestinal immunity, Beijer et al. [13] set out to examine whether vitamin A influences the splenic DC composition and made the intriguing discovery that, relative to splenic CD8+ DCs (CD11bloCD4−CD8hi), splenic CD4+ DCs (CD11bhiCD4hiCD8−), and splenic DN DCs (CD11bhiCD4−CD8−) have

elevated expression of a number of RA target genes (MMP9, gp91hox, and TG2). It was also observed that CD4+ DCs and DN DCs express gene signatures indicative of preferential RA metabolism and utilization. www.selleckchem.com/products/Y-27632.html To determine whether these RA responsive elements in CD4+ DCs and DN DCs reflect developmental or functional dependencies on vitamin A, the authors fed newborn mice (day 7.5–10 of gestation) a vitamin A-deficient diet and analyzed the relative proportion of the three DC subsets in the spleen after at least 9 weeks of diet. Strikingly, while the relative proportion of CD8+ DCs remained

unaffected by the absence of RA, there was a significant reduction in the proportion of both CD4+ DCs and DN DCs. Collectively, this suggests that in contrast LDK378 purchase to CD8+ DCs, CD11bhi

DCs are subject to RA signaling and that these signaling events are necessary for their differentiation within the spleen. To further probe the activity of RA in shaping the differentiation of splenic DCs, Beijer et al. [13] performed the reverse experiment, placing mice on a RA-rich diet before examining the relative proportion of the three DC subsets in the spleen. Here, excessive RA resulted in a shift toward DN DCs. Specifically, the frequency of CD11bhi DN DCs increased dramatically in the spleen, while the proportion of CD8+ DCs and, unexpectedly, CD4+ DCs was significantly suppressed in mice fed the vitamin A-rich diet. The lack of an increase in CD4+ DCs in response to RA overexposure and Bacterial neuraminidase subtle, but significant differences in the expression patterns of some of the nuclear RA receptors (RXRα, RARα, RXRβ) between CD4+ DCs and DN DCs are likely related to heterogeneity within the CD11bhi DC population. Indeed, when Beijer et al. [13] segregated CD11bhi DCs on the basis of ESAM expression, which has recently been shown to resolve two distinct subsets within the CD11bhi DC population [11], they noted that RA specifically affected ESAMhi CD11bhi DCs with this subset being selectively reduced in the absence of RA and increased upon overexposure to RA.

CD4−CD16+ NK cells showed upregulation of the activation marker NKG2D (Fig. 5A and Kinase Inhibitor Library cost D) after co-incubation with iTreg cells. While the inhibitory KIRs CD158a and CD158b were not modulated on NK cells (Fig. 5B), the expression of perforin was clearly enhanced after co-culture with iTreg cells (Fig. 5C and D). These data indicate that iTreg cells are able to activate NK cells resulting in the upregulation of NKG2D and perforin in the absence of IL-2 pre-stimulation. In summary, our findings thus far demonstrate that iTreg cells impair IL-2-mediated NK activation, provided that NK cells have no target cell contact. In contrast, target cell-induced NK

activation is enhanced by iTreg cells. In the final series

of experiments, we investigated NK activation induced by a combination of IL-2 and target cell contact. Under these conditions, NK degranulation was induced from 8 to 26% (p=0.02) compared with resting NK cells (Fig. 6). Induced Treg cells further promoted this NK cell function compared with IL-2-activated NK cells with tumors alone (from 26 to 54%; p=0.01, Fig. 6). In contrast, nTreg cells did not further modulate degranulation of IL-2-activated NK cells towards target cells. In agreement with previous reports, we found that IL-2 induces activation of primary human peripheral blood NK cells resulting in upregulation of activating receptors, NKG2D and NKp44, as well as increased degranulation and IFN-γ secretion

21, 22. These effects were significantly impaired in the presence of tumor iTreg cells, nTreg cells or TGF-β. Our results are in agreement with published Atezolizumab reports, where other types of Treg cells were described to suppress NK cell functions under various experimental conditions, in most instances in a TGF-β-dependent 3-mercaptopyruvate sulfurtransferase manner 11, 12, 19, 23–27. Unexpectedly, we found that degranulation and the subsequent tumoricidal activity of naive NK cells were enhanced by iTreg cells. iTreg cell-enhanced cytotoxicity of NK cells was perforin- and FasLigand-dependent, while death receptor TRAIL was not involved. Consistent with the upregulation of activating receptors NKG2D and NKp44, the expression of inhibitory KIRs CD158a and CD158b on NK cells remained at basal levels in the co-culture with tumor iTreg cells. In conjunction, these data suggest that tumor iTreg cells negatively interfere with IL-2-mediated NK-cell activation, while the IL-2-independent activation of NK cells by target cell contact is augmented in the presence of iTreg cells. Importantly, the activation of NK cells by a combination of IL-2 and target cell contact is further promoted in the presence of iTreg cells. It is well established that NK cells activated by IL-2 are highly cytolytic to many tumor targets and thus NK cell-activating cytokines like IL-2 are frequently incorporated into current immunotherapeutic strategies and clinical trials 28.

Both of these hospitals are major central referral centers to which many patients from other areas of Iran are referred. In all, 183 immunocompromised patients were included in this study. Eligibility criteria Vismodegib order were immunosuppression

due to HIV infection (with decreased white cell counts), hematological malignancies and use of immunosuppressive drugs after solid organ transplant or for treatment of chronic or intractable hematologic diseases. The ethics committee of Baqiyatallah University of Medical Sciences approved the study protocol. After informed written consent had been obtained, the study nurse administered a comprehensive questionnaire to each patient. This author-compiled checklist included items on patient variables including age, sex and weight; sociodemographic and intra-familial factors; location of dwelling; occupation; number of household members with diarrhea; zoonotic factors including exposure to pets and farm animals; and environmental factors including source of drinking water and exposure Small molecule library to lake, river or swimming pools. Clinical characteristics including diarrhea, weight loss, vomiting, abdominal pain and nausea, presence of concomitant microbial infections, antiretroviral use and laboratory characteristics including CD4 + T-cell counts were recorded. This checklist was filled out

by a physician who confirmed patient’s symptoms by physical examination and so on. Diarrhea was defined as three or more watery or loose stools in a 24-hour period. Diarrhea that persisted for more than two weeks was considered chronic; otherwise, it was classified as acute. Weight loss was considered significant when referred patients lost more than 10% of their baseline body weight during their hospitalization. Three fecal samples were collected at two days intervals from each patient and placed in a disposable plastic cup. The samples were taken immediately to the laboratory and stored at −20°C until analysis. The fecal specimens were concentrated using a sucrose solution with a specific gravity of 1.200 at a centrifuge speed of 800

×g for 10 mins. All samples were stained by the modified Ziehl-Neelsen method and examined under Progesterone bright field microscopy. A sample was considered Cryptosporidium positive if typical oocysts 4–6 μm in diameter were visible. Fecal samples were subjected to six cycles of freeze–thaw in liquid nitrogen and a 95°C water bath to rupture the oocysts. DNA was isolated from aliquots of frozen stool using the QIAamp DNA stool minikit (Qiagen, Gaithersburg, MD, USA) according to the manufacturer’s instructions. A two-step nested PCR protocol was used to amplify the 18S rRNA gene (830 bp). The fragment of the 18S rRNA gene was amplified by PCR using the following primers: 5′-TTCTAGAGCTAATACATGCG-3′ and 5′-CCCATTTCCTTCGAAACAGGA-3′ for primary PCR and 5′-GGAAGGGTTGTATTTATTAGATAAAG-3′ and 5′-AAGGAGTAAGGAACAACCTCCA-3′ for secondary PCR.

Some of the most frequently studied HDPs are the cathelicidins, including human LL-37 and its rodent ortholog mouse cathelin-related antimicrobial peptide (mCRAMP). Cathelicidins are characterized by a conserved cathelin pro-domain located near the N-terminus that is removed as the peptide is secreted, leaving the active HDP 1, 5. It is well known that cathelicidins and other HDPs influence adaptive immunity by acting on APCs (Fig. 1). Cathelicidins are secreted and taken up by macrophages, B cells, and DCs and their effects on these cells lead to selective

immune activation 1, 2, 6. Immature monocyte-derived DCs (MDDCs) transport LL-37 into the cytoplasm and nucleus, MLN0128 order where LL-37 acts to upregulate CD86 and HLA-DR expression 7. MDDCs derived in the presence of LL-37 also show various changes in surface expression including increased CD86 and CD11b in immature MDDCs 8. These markers are associated with activation of the adaptive response; however, in response to Toll-like receptor (TLR) ligands, including lipopolysaccharide (LPS), cathelicidins can limit DC activation. For example, a model of allergic contact dermatitis found that wild-type mice had significantly decreased DC maturation and inflammation

in response to LPS sensitization as compared with mice lacking mCRAMP 9. Kandler et al. 10 found that LPS and other TLR ligands Dabrafenib concentration in combination with LL-37 led to a decrease in expression of HLA-DR, CD86, and other markers when applied to DCs. else When such DCs were co-cultured with CD4+ T cells, this reduced T-cell proliferation and their production of the T-cell activators IL-2 and IFN-γ 10. Conversely, MDDCs derived with LL-37 in the culture medium showed normal maturation and increased CD11b

and CD86 expression in response to LPS, and co-cultured T cells exposed to LPS and LL-37 had increased IFN-γ production but no significant change in cell proliferation 8, consistent with the concept that HDPs modulate rather than suppress or stimulate immune responses. Other APCs include the M1 and M2 macrophages, polarized to a pro- and anti-inflammatory response, respectively. M1 macrophages promote the maturation of naïve CD4+ T cells into Th1 cells, leading to activation of cell-mediated immunity, whereas M2 macrophages promote the development of Th2 cells and the humoral response. Both M1 and M2 macrophages show decreased TNF-α production in response to LL-37 11, but LL-37 has also been demonstrated to make M2 macrophages more pro-inflammatory 12. Together, these studies show that immune responses to cathelicidins depend on when the cathelicidin is applied and the presence of other signaling molecules such as TLR ligands. While cathelicidins clearly influence APCs and their interactions with adaptive immune cells, evidence is emerging that cathelicidins have a more direct influence on the adaptive response.