Author response: Cytotoxic CD4+ T cells driven by T-cell intrinsic IL-18R/MyD88 signaling predominantly infiltrate Trypanosoma cruzi-infected hearts
Year: 2022
Type: peer-review
Abstract: Article Figures and data Abstract Editor's evaluation Introduction Results Discussion Materials and methods Data availability References Decision letter Author response Article and author information Metrics Abstract Increasing attention has been directed to cytotoxic CD4+ T cells (CD4CTLs) in different pathologies, both in humans and mice. The impact of CD4CTLs in immunity and the mechanisms controlling their generation, however, remain poorly understood. Here, we show that CD4CTLs abundantly differentiate during mouse infection with the intracellular parasite Trypanosoma cruzi. CD4CTLs display parallel kinetics to Th1 cells in the spleen, mediate specific cytotoxicity against cells presenting pathogen-derived antigens and express immunoregulatory and/or exhaustion markers. We demonstrate that CD4CTL absolute numbers and activity are severely reduced in both Myd88-/- and Il18ra-/- mice. Of note, the infection of mixed-bone marrow chimeras revealed that wild-type (WT) but not Myd88-/- cells transcribe the CD4CTL gene signature and that Il18ra-/- and Myd88-/- CD4+ T cells phenocopy each other. Moreover, adoptive transfer of WT CD4+GzB+ T cells to infected Il18ra-/- mice extended their survival. Importantly, cells expressing the CD4CTL phenotype predominate among CD4+ T cells infiltrating the infected mouse cardiac tissue and are increased in the blood of Chagas patients, in which the frequency of CD4CTLs correlates with the severity of cardiomyopathy. Our findings describe CD4CTLs as a major player in immunity to a relevant human pathogen and disclose T-cell intrinsic IL-18R/MyD88 signaling as a key pathway controlling the magnitude of the CD4CTL response. Editor's evaluation This is an interesting study, conducted in mice, that demonstrates for the first time the presence of a large population of cytotoxic CD4+ T lymphocytes in infection with Trypanosoma cruzi, a relevant human pathogen. At present, the relevance of these cells in protective immunity engendered by the host remains unclear. Additional experiments are needed to characterize the functionality of these cytotoxic CD4 T cells vis-a-vis the canonical Th1 T cells. This paper can be of interest to scientists interested in immune responses to parasitic infections. https://doi.org/10.7554/eLife.74636.sa0 Decision letter Reviews on Sciety eLife's review process Introduction Cytotoxic CD4+ T cells (CD4CTLs) are present in viral infections, cancer and autoimmune diseases (Cheroutre and Husain, 2013; Juno et al., 2017; Takeuchi and Saito, 2017). Although more frequently found in chronic conditions, CD4CTLs have also been described during acute viral infection (Brien et al., 2008; Brown et al., 2012; Fang et al., 2012; Jellison et al., 2005; Wilkinson et al., 2012). At present, however, there are few studies on the CD4CTL response to infection with non-viral intracellular pathogens (Burel et al., 2016; Canaday et al., 2001; Kotov et al., 2018; Krueger et al., 2021). The role of CD4CTLs in immunity against intracellular parasites and the mechanisms operating in the generation and maintenance of this cell subset are poorly understood. Following the recognition of the cognate antigen-MHC complex and under the influence of cytokines secreted by antigen presenting cells (APCs), naïve CD4+ T cells proliferate and differentiate into diverse subsets, including Tfh, Th1, Th2, or Th17, with varied effector functions. Different pathogen-derived molecular patterns (PAMPs) elicit distinct innate immune pathways, resulting in tailored Th responses against the infectious agent (Kara et al., 2014). Interestingly, single-cell heterogeneity in the transcriptional profile of effector CD4+ T cells, dictated in a microbe-specific manner, has been recently found in the gut (Kiner et al., 2021). Additionally, tissue-derived factors can also be involved in defining CD4+ T cell phenotypes (Poholek, 2021). In this context, the mechanism regulating the differentiation of CD4CTLs remains an open and relevant question. Although some authors consider CD4CTLs functional variants of Th1 cells, there is also evidence that CD4CTLs might constitute a Th1-independent subset, directly differentiating from naïve CD4+ T cell precursors or even a heterogeneous population congregating cytolytic lymphocytes that originate from different T-cell subsets, such as Treg, Th1, and Th2 cells (reviewed in Cheroutre and Husain, 2013 and Takeuchi and Saito, 2017). Receptors belonging to the TLR and IL-1R families are upstream of the MyD88 adaptor molecule and are expressed both in myeloid and lymphoid cell lineages. MyD88-dependent signaling in innate cells can influence Th1 cell differentiation by inducing the release of IL-12 or IFN-γ (Joffre et al., 2009; Takeda et al., 1998). The T-cell intrinsic MyD88 adaptor function was also shown to be essential for the Th1 response in different contexts. The identity of the receptor acting upstream of MyD88 on T cells, however, was not always determined (Frazer et al., 2013; LaRosa et al., 2008) and remains a matter of debate. Early in vitro studies have shown that IL-18 synergizes with IL-12 in the induction of IFN-γ production and T-bet expression by CD4+ T cells and, therefore, impacts Th1 development (Robinson et al., 1997). Intriguingly, the IL-18 contribution for a robust Th1 response in vivo has not always been confirmed (Haring and Harty, 2009; Monteforte et al., 2000). ST2 (IL-33 receptor) and IL-1R have also been implicated in the establishment of Th1 responses to viral infection (Baumann et al., 2015) and immunization (Ben-Sasson et al., 2009; Schenten et al., 2014), respectively. Previously, our group identified the crucial role of T cell-intrinsic IL-18R/MyD88 signaling for the reinforcement and maintenance of the Th1 program in vivo, in response to mouse infection with Trypanosoma cruzi, in which Th1 cells have a key protective function (Oliveira et al., 2017; Rodrigues et al., 2012). T. cruzi is an intracellular protozoan parasite and the etiologic agent of Chagas disease (American trypanosomiasis), one of the most important parasitic diseases in the Western Hemisphere. Chagas disease is an important cause of heart failure, stroke, arrhythmia, and sudden death, being the leading cause of cardiomyopathy among younger individuals in Latin America (Bern, 2015; Nunes et al., 2018). Here we showed that CD4+ T lymphocytes with a CTL phenotype are abundantly present in the spleen of mice infected with T. cruzi and display in vitro and in vivo Ag-specific cytotoxicity against APCs. Of note, we found that cells with a CTL phenotype predominate among CD4+ T lymphocytes infiltrating infected cardiac tissue. Using mixed bone marrow (mix-BM) chimeras, we show that T cell-intrinsic IL-18R/MyD88 signaling plays a crucial role for the expansion/survival of CD4+ T cells expressing the CTL gene signature in vivo. In accordance with results obtained in mix-BM chimeras, we found that absolute numbers of CD4 T cells displaying cytotoxic markers and activity were severely reduced in Myd88-/- and Il18ra-/- mouse lineages. Moreover, adoptive transfer of wild-type (WT) CD4+GzB+ T cells to Il18ra-/- mice increase survival of this susceptible mouse strain to infection. Interestingly, the majority of CD4+GzB+ T cells in WT infected mice express high levels of immunoregulatory molecules such as, Tim-3, Lag-3, CD39, and PD-1. Finally, and importantly, we detected the presence of CD4+ T cells expressing perforin in the blood of patients with the severe cardiac form of Chagas disease and correlation analyses point to a possible pathogenic role of these cells in the chronic phase of Chagas myocarditis. To our knowledge, the present study is the first to extensively characterize CD4CTLs generated in response to a protozoan pathogen in a murine model and to elucidate a central mechanism that accounts for their expansion/survival. Results CD4+ T cells with cytolytic phenotype are abundantly present in the spleen of mice infected with T. cruzi CD4CTLs express granzyme B (GzB) and perforin (PRF), which are major constituents of CD8CTL and NK cell-granules that promote target cell death in a number of ways (Afonina et al., 2010). Here, we reveal the presence of a TCRαβ+CD8α-NK1.1-CD4+GzB+ T cell population, which represents around 30% of the CD4+ T cells in the spleen of C57BL/6 (B6) mice, in the acute phase of infection with T. cruzi (Figure 1A and B and Figure 1—figure supplement 1A). Equivalent percentages of CD4+PRF+ T cells were found (Figure 1C) and the majority of CD4+GzB+ T cells express PRF and the cytolytic marker 2B4 (CD244) (Figure 1D and E). Of note, most CD4+GzB+ T cells (>80%) do not express IFN-γ at day 14 post-infection (pi), the peak time-point of the T cell response, and although CD4GzB+ and CD4IFN-γ+ cells follow similar kinetics in the spleen, the absolute number of CD4+GzB+ T cells was superior to that of CD4+IFN-γ+ cells, at every time point of the infection (Figure 1F and G). It is known that intracellular parasitism by T. cruzi Y strain in the spleen is at its highest point between day 12 and 15 pi, concomitant with the histologically observed massive destruction of parasitized splenic macrophages (Cordeiro et al., 1997). Therefore, there is a coincidence between parasite titers in the spleen and the frequency and absolute numbers of CD4+GzB+ T cells. We also observed an increase in the percentage of degranulating CD4+ T cells at day 14 pi, comparable to the CD8+ T cells, as inferred by staining with anti-CD107a (LAMP-1) mAb, (Figure 1H), although CD8CTLs are present at higher percentage (Figure 1—figure supplement 1B-E and G ) and absolute number (Figure 1—figure supplement 1F and H). In summary, these data show the remarkable induction of CD4+ T cells with cytolytic potential during infection with T. cruzi, an effector subpopulation whose appearance in the spleen parallels and largely outnumbers that of classic GzB- IFN-γ+ Th1 cells. Figure 1 with 1 supplement see all Download asset Open asset CD4+GzB+PRF+ T cells are present at high frequency in the spleen of mice infected with T. cruzi. (A) CD4+ T cell gating strategy. (B and C) Representative flow-cytometry dot plots of granzyme B (GzB) (B) or perforin (PRF) (C) staining, gated on CD4+ T cells from non-infected (naïve) or infected B6 mice (left) and mean frequency of CD4+GzB+ (or CD4+PRF+) T cells in the spleen (right). (D) Representative dot plots of PRF and GzB expression in CD4+ T cells gated as in (A) and mean frequencies of PFR+ among GzB+ CD4+ T cells (isotype controls on Figure 1—figure supplement 1A). (E) Representative histogram of 2B4 (CD244) expression on CD8+ (blue), CD4+GzB+ (red) or CD4+GzB- T cells (pink), and correspondent mean fluorescence intensity (mean MFI) values; (F) Representative dot plots of GzB and IFN-γ staining in gated CD4+ T splenocytes (left), mean frequencies of GzB+IFN-γ- (red), GzB+IFN-γ+ (purple) and GzB-IFN-γ+ (blue) subsets among total CD4+ (center) or gated on CD4+GzB+ T cells (right). (G) Kinetics of the mean frequency of CD4+IFN-γ+ (purple) and CD4+GzB+ (red; left), and corresponding absolute numbers (right). (H) Frequency of LAMP-1+(CD107a+) cells among CD4+GzB+ (red) or CD8+GzB+ (blue) T cells in the infected spleen. Data obtained from individually analyzed mice (n=4), at indicated or 14 day post-infection (pi). Error bars = SEM. ND = non-detected. ns = non-significant; **p≤0.01 (Student’s t-test). Data are representative of three or more independent experiments. CD4+ T cells from infected spleen exert Ag-specific cytotoxicity To ascertain the presence of CD4+ T lymphocytes with cytolytic function, we performed a redirected cytotoxicity assay, with anti-CD3 mAb–coated B cell blasts as target cells that were co-incubated with either highly purified effector (CD44hi) CD4 T cells sorted from the spleen of infected mice or naive (CD44lo) CD4 T cells from non-infected controls. The CTL activity was observed only when effector CD4+ T cells were employed (Figure 2A). In order to determine if the CD4CTL killing capability is dependent on GzB- and PRF-mediated killing, we performed the cytotoxic assays in the presence of the GzB and PRF inhibitors, Z-AAD-CMK and Concamycin A, respectively. As shown in Figure 2—figure supplement 1A, the killing of target cells was abolished in this condition, demonstrating that the cytolysis mediated by CD4CTLs in T. cruzi-infected mice depends on GzB and PRF, as previously shown for tumor-specific CD4CTLs (Quezada et al., 2010). Antigen-specific cytotoxicity, using highly purified CD4+ T cells, was also assayed in vitro against an I-Ab+ macrophage cell line (IC-21), loaded or not with T. cruzi amastigote total protein extract. Results shown in Figure 2B and Figure 2—figure supplement 1B demonstrate that CD4CTLs with cognate cytotoxic activity are present in the spleen of infected mice. FasL is expressed on CD8+ and CD4+ T cells at the immunological synapse following Ag-triggered degranulation and participates in CD4CTL-mediated lysis of target cells (Bossi and Griffiths, 1999; Brown et al., 2009; Kotov et al., 2018). As shown in Figure 2B, addition of anti-FasL mAb significantly inhibited the specific lysis of the target cells, demonstrating the involvement of the FasL/Fas pathway in the killing process. Figure 2 with 3 supplements see all Download asset Open asset CD4 T cell-mediated Ag-specific cytotoxicity and transcription factor (TF) expression by CD4+GzB+ T cells. (A) Mean frequencies of dead target cells (LPS-induced B blasts) in redirected cytotoxicity assay employing sorted naïve (blue) or in vivo activated (red) CD4+ T cells as effectors, at different E:T ratios, in triplicates. (B) Specific lysis of IC-21 macrophages (T) loaded with amastigote antigens, co-incubated with highly purified effector CD4+ T cells, at the indicated E:T ratios, in the presence of anti-FasL mAb (red) or isotype control mAb (blue). Mean values of triplicates ± SEM are shown in (A) and (B); *p≤0.05 (two-tailed Student’s t-test). Data are representative of three independent experiments. Gating strategy on Figure 2—figure supplement 1B. (C and D) Percentages of Ag-specific cytotoxicity in vivo; bars represent mean values + SEM (error bars) of individually analyzed mice (n=3) infected with T. cruzi Y in (C) or ovalbumin (OVA)-expressing Y strain trypomastigotes (Y-OVA) strain in (D); class I-restricted (PA8 or OVA257-264) and class II-restricted (SA851.1c+d or OVA323-339) peptides were employed. Data are representative of two independent experiments. Cell survival was measured by flow cytometry (Figure 2—figure supplement 1C) and specific lysis calculated as described in Methods. (E and F) Representative dot plots of CD4+ T cells (gated as in Figure 1A) and corresponding mean frequencies of gated subpopulations: (E) granzyme B (GzB) and FoxP3 staining and (F) GzB and T-bet staining. (G) Representative histogram of Eomes expression in CD4+ T splenocytes of non-infected mice (ctr, gray) and in GzB- (black) and GzB+ (red) CD4+ T cells from infected mice, gated as in Figure 1A and B (left) and mean frequencies of Eomes+ cells among these different subpopulations (right). All experiments were done at day 14 post-infection (pi). Bars represent mean values of non-infected ctr group n=3 or infected group, n=3–5, individually analyzed mice. Error bars = SEM. (H) Runx3d and ThPOK (Zbtb7b) mRNA expression estimated by qRT-PCR in CD4+EYFP+ T cells sorted from infected and tamoxifen-treated GzmbCreERT2/ROSA26EYFP mice, as described in Methods and shown in Figure 2—figure supplement 3A; ND = not detected. Mean values of triplicates + SEM are shown. Data are representative of three independent experiments. We tested the in vivo killing of target splenocytes loaded with class II-restricted peptides (SA85-1.1c and d), derived from a protein of the T. cruzi transialidase superfamily (Millar and Kahn, 2000; Figure 2C and Figure 2—figure supplement 1C). The detailed Ag-specific repertoire of CD4CTLs could not be further assessed because of the scarce definition of parasite-derived CD4 epitopes in the literature. To circumvent this, we infected mice with ovalbumin (OVA)-expressing Y strain trypomastigotes (Y-OVA) (Gomes-Neto et al., 2018) and compared the in vivo cytotoxic response against known OVA-derived CD4 and CD8 epitopes: OVA323-339 and OVA257-264, respectively. As shown in Figure 2D, the same level of specific killing was attained against targets loaded with class I- or class II-restricted OVA peptides. Together, these experiments confirmed the presence of a CD4+ T cell population with Ag-specific cytolytic function against MHC class II-restricted epitopes in the spleen of mice infected with T. cruzi. CD4+GzB+ T cells express transcription factors typical of CTLs We then investigated the expression of transcription factors (TFs) typical of cytotoxic CD8 T cells. T-bet and Eomesodermin (Eomes) are known to bind to the promoters of Gzmb and Prf1 (Glimcher et al., 2004; Intlekofer et al., 2005; Pearce et al., 2003) and were shown to be expressed in CD4CTLs (Curran et al., 2013; Eshima et al., 2012; Qui et al., 2011). Figure 2E and F show that the vast majority of CD4+GzB+ T cells express T-bet, but not FoxP3, the master gene of Treg cells. In accordance with the cytolytic potential of CD4+GzB+ T cells in our model, 60% of the CD4+GzB+ T cells express Eomes, while only a small percentage of GzB- CD4+ T cells are Eomes+ (Figure 2G). Of note, at day 14 pi, the vast majority of both GzB+ and GzB- CD4+ T lymphocytes are CD44hiCD62Llo effector/memory cells (Figure 2—figure supplement 2). CD4CTLs that migrate to the gut, gradually stop expressing ThPOK, while upregulating the expression of RUNX3 (Mucida et al., 2013; Reis et al., 2013), which is known to drive the CTL gene program in CD8+ T cells (Cruz-Guilloty et al., 2009; Egawa et al., 2007). The long-form transcript encoding RUNX3 (Runx3d) is also expressed in Th1 cells, but not in Th2 or naïve cells (Djuretic et al., 2007). As shown in Figure 2H, besides Runx3d mRNA, we found that CD4+GzB+ T cells, sorted from the spleen of tamoxifen-treated infected GzmbCreERT2/ROSA26EYFP reporter mice (Bannard et al., 2009; Figure 2—figure supplement 3A), express ThPOK (Zbtb7b gene)-coding RNA comparable to naive CD4+ T cells, at day 14 pi, when their number and frequency are at the highest levels in this organ (Figure 1G). The absence of CD8α-coding transcripts confirms the purity of sorted CD4+GzB+ T cells (Figure 2—figure supplement 3B). a large of CD4+GzB+ T cells do not express in the infected reporter mice and, as a we could not GzB- CD4+ T cells, was not possible to the levels of Runx3d expression between GzB+ and subsets of activated CD4+ T cells. data show that CD4+GzB+ T cells generated in response to infection with T. cruzi, besides expressing cytolytic also express T-bet, Eomes and typical found in cytotoxic T cells. CD4+GzB+ T cells express cytotoxic markers and immunoregulatory molecules cells are a subset of T cells that express GzB and PRF and exert a function both in humans and mice et al., 2018). a high percentage of CD4+GzB+ T cells in our express Eomes, which the development of cells et al., we investigated T. CD4+GzB+ T cells with cells. We detected a frequency of T cells in the of mice infected with T. cruzi, in with data et al., although cells were found to be more among CD4+GzB+ T cells (Figure and Figure supplement 1A, The of and both human and mouse cells et al., Although most splenic CD4+GzB+ T cells express Lag-3, only a percentage of these cells (Figure and and Figure supplement 1C). the a of splenic CD4+GzB+ T cells express the immunoregulatory molecule and (Figure and that these might be cells, as in et al., 2016; Takeuchi and Saito, 2017). Figure 3 with supplements see all Download asset Open asset of immunoregulatory molecules and cytotoxic markers by CD4+GzB+ T cells. (A) Representative dot plots of staining and mean frequencies of cells among non-infected (ctr, gray) or granzyme and GzB+ (red) CD4+ T cells from infected mice. (B) Representative histogram of staining and mean frequency of cells. (C) Representative dot plots of and staining and mean frequency of different cells (D) Representative histogram of staining and mean frequency of cells among different cells (E) Representative histogram of staining and mean frequency of cells. CD4+GzB+ T cells gated as in Figure 1A, staining controls in Figure supplement Representative dot plots and mean frequencies of (F) (G) and (H) expression among gated CD4+ T All experiments were done at day 14 post-infection (pi). ctr group, infected group, mice, individually Error bars = (two-tailed Student’s t-test). Data are representative of three independent experiments. controls are shown on Figure supplement group 2 A, and are and cytotoxic markers expressed by and activated CD8+ T cells et al., 2004; et al., 2018). and molecules a CD4CTL population, present in mouse during infection et al., 2017). As shown in Figure and G the of cells expressing and was increased among splenic CD4+GzB+ T cells, when compared to either GzB- CD4+ T cells of infected mice or to naive CD4+ T cells of non-infected controls (Figure supplement and The class I-restricted T cell molecule was described as being for the differentiation of CD4CTLs et al., 2016; Takeuchi and Saito, 2017). Figure that the frequency of cells was also increased among splenic CD4+GzB+ T cells of T. cruzi-infected mice, when compared with GzB- CD4+ T cells. We then analyzed and cytotoxic markers were on T cells. As shown in Figure supplement while most cells also express the cytotoxic only a of CD4+GzB+ T cells and The frequencies of and CD8+GzB+ T cells in infected mice are shown in Figure supplement as shown in Figure 2—figure supplement both GzB- and GzB+ CD4+ T cells are in their majority effector/memory cells at day 14 pi, results were obtained gating on cells or not (Figure supplement Together, these results show that a of the CD4+GzB+ T cell subpopulation found in this parasite infection model with the phenotype of CD4CTLs and in response to viral infection. CD4CTLs are present in numbers in Myd88-/- infected mice To our on the for the differentiation of CD4CTLs and their to Th1 cells, we investigated the role of IFN-γ and MyD88 in their IL-12 and IFN-γ are the major cytokines Th1 differentiation and T-bet but their for CD4CTL generation is et al., 2009; et al., 2004; et al., 2013; et al., 2013; Kotov et al., 2018; Krueger et al., et al., 2016; et al., 2010). Here, we observed that mice infected with T. cruzi percentages of and T cells and levels of CD4+GzB+ T cells (Figure Interestingly, in infected mice, the frequency of T cells, CD4+GzB+ T cells attained the same frequencies as observed in the of WT (Figure absolute numbers of both total CD4+ and CD4+GzB+ T cells were in mice when compared to WT controls. both and IFN-γ important but distinct in the differentiation and expansion/survival of CD4+GzB+ T cells. Figure with 2 supplements see all Download asset Open asset Cytotoxic CD4+ T cells (CD4CTLs) are severely reduced in Myd88-/- mice. Representative dot plots of granzyme B (GzB) and T-bet staining on gated CD4+ T splenocytes and mean frequencies of IFN-γ+ and GzB+ CD4+ T cells and absolute numbers of T cells the from (A) wild-type (B6) and mice on day 14 post-infection and (B) wild-type (WT) and mice on day (C) Representative dot plots and gating strategy. (D) Mean frequencies and (E) absolute numbers of GzB+ or and cells among T cells in the spleen of WT (blue) and Myd88-/- (red) mice at day Bars represent mean values in each individually analyzed mice. Error bars = ns = non-significant; (Student’s t-test). Representative dot plots of and staining on CD4+ T cells from non-infected are shown in Figure supplement 1B. (left) and absolute numbers of cells among CD4+ T cells (F) and of cells among T cells (G) in the spleen of non-infected or infected WT bars) and Myd88-/- bars) mice. T cells were gated as shown in Figure Data in (F) and (G) are from independent experiments with n=3 in each group, each represents an analyzed mice. (Student’s t-test). (H) Frequency of dead target cells (LPS-induced B cell blasts) in cytotoxic assay, 14 of with T cells sorted from WT or Myd88-/- infected mice at day B cells were with anti-CD3 (left) or not (right). Mean of triplicates SEM for each E:T point are shown. Data are representative of three independent experiments. The results obtained in and mice, with the that Myd88-/- mice have levels of Th1 cells and are highly susceptible to infection with T. cruzi et al., 2004; et al., to the role of MyD88-dependent in the generation of Although infected Myd88-/- mice absolute numbers and percentages of total splenic CD4+ T cells when compared to WT mice (Figure supplement the frequencies and absolute numbers of CD4+GzB+ T cells were significantly in this mouse strain (Figure absolute numbers of and CD4+GzB+ T cells were severely in Myd88-/- mice (Figure This not from numbers of total activated CD4+ T cells in infected Myd88-/- mice, as shown by the percentages and absolute numbers of cells, which are to observed in WT (Figure supplement 2). the absolute numbers of and CD8+GzB+ T cells were not in Myd88-/- mice (Figure supplement the expression of both the percentages and absolute numbers of T cells were also severely in Myd88-/- compared to WT mice (Figure The same was observed when the frequency and absolute numbers of T cells among cells (Figure In order to to the absence of MyD88 expression impact on cytotoxicity mediated by CD4+ T we sorted activated T cells from both WT and Myd88-/- infected mice to a high purity level and performed redirected cytotoxicity levels of cytotoxicity were observed when sorted Myd88-/- T cells were as compared to assays using numbers of sorted WT T cells (Figure Together, these results demonstrate the important role of MyD88 signaling for the establishment of a robust cytotoxic response mediated by T cell-intrinsic IL-18R/MyD88 signaling plays a crucial role in the establishment of a CD4+ T cell subpopulation the CD4CTL gene signature MyD88 results in IL-12 production by et al., and this could the numbers of CD4CTLs found in infected Myd88-/- mice. we have recently shown that IL-18R/MyD88 signaling intrinsic to CD4+ T cells is for Th1 cell and to in response to infection with T. cruzi (Oliveira et al., 2017). CD4CTLs described a differentiation process with (or Th1 cells, is to that besides IL-12 and MyD88-dependent signaling also be important for the generation of a robust CD4CTL response. In order to this we mix-BM chimeras in which WT mice were and with a
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Subfield: Epidemiology
Field: Medicine
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