HCA587 protein vaccine induces specific antitumor immunity mediated by CD4+ T-cells expressing granzyme B in a mouse model of melanoma

2020 ◽  
Vol 20 ◽  
Author(s):  
Weiming Yang ◽  
Weiheng Zhang ◽  
Xiaozhong Wang ◽  
Liming Tan ◽  
Hua Li ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Antitumor Effect ◽  
Granzyme B ◽  
Cell Subset ◽  
Cell Mediated Immunity ◽  
Protein Vaccine ◽  
Tumor Tissues ◽  
Wide Range ◽  
Ifn Γ

Background: The antigen HCA587 (also known as MAGE-C2), which is considered a cancer-testis antigen, exhibits upregulated expression in a wide range of malignant tumors with unique immunological properties, and may thus serve as a promising target for tumor immunotherapy. Objective: To explore the antitumor effect of the HCA587 protein vaccine and the response of humoral and cell-mediated immunity. Methods: The HCA587 protein vaccine was formulated with adjuvants CpG and and ISCOM. B16 melanoma cells were subcutaneously inoculated to C57BL/6 mice, followed by treatment with HCA587 protein vaccine subcutaneously. Mouse survival was monitored daily, and tumor volume was measured every 2 to 3 days. The tumor sizes, survival time and immune cells in tumor tissues were detected. And the vital immune cell subset and effector molecules were explored. Results: After treatment with HCA587 protein vaccine, the vaccination generated elicited significant immune responses, which delayed tumor growth and improved animal survival. The vaccination increased the proportion of CD4+ T cells expressing IFN-γ and granzyme B in tumor tissues. Depletion of CD4+T cells resulted in an almost complete abrogation of the antitumor effect of the vaccination, suggesting that the antitumor efficacy was mediated by CD4+ T cells. In addition, knockout of IFN-γ resulted in a decrease in granzyme B levels which were secreted by CD4+ T cells, and the antitumor effect was also significantly attenuated. Conclusion: The HCA587 protein vaccine may increase the levels of granzyme B expressed by CD4+ T cells, and this increase is dependent on IFN-γ, and the vaccine resulted in a specific tumor immune response and subsequent eradication of the tumor.

scholarly journals Circulating CD4 T cells elicited by endemic coronaviruses display vast disparities in abundance and functional potential linked to both antigen specificity and age

2021 ◽  
Author(s):  
Katherine A Richards ◽  
Maryah Glover ◽  
Jeremy C Crawford ◽  
Paul Thomas ◽  
Chantelle White ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Protective Immunity ◽  
Granzyme B ◽  
Antigen Specificity ◽  
Functional Potential ◽  
Membrane Envelope ◽  
Ifn Γ ◽  
Human Coronaviruses ◽  
Repeated Infections

Abstract Repeated infections with endemic human coronaviruses are thought to reflect lack of long-lasting protective immunity. Here, we evaluate circulating human CD4 T cells collected prior to 2020 for reactivity towards hCoV spike proteins, probing for the ability to produce IFN-γ, IL-2 or granzyme B. We find robust reactivity to spike-derived epitopes, comparable to influenza, but highly variable abundance and functional potential across subjects, depending on age and viral antigen specificity. To explore the potential of these memory cells to be recruited in SARS-CoV-2 infection, we examined the same subjects for cross-reactive recognition of epitopes from SARS-CoV-2 nucleocapsid, membrane/envelope, and spike. The functional potential of these cross-reactive CD4 T cells was highly variable, with nucleocapsid-specific CD4 T cells, but not spike-reactive cells showing exceptionally high levels of granzyme production upon stimulation. These results are considered in light of recruitment of hCoV-reactive cells into responses of humans to SARS-CoV infections or vaccinations.

scholarly journals Listeria monocytogenes as a Short-Lived Delivery System for the Induction of Type 1 Cell-Mediated Immunity against the p36/LACK Antigen of Leishmania major

2000 ◽  
Vol 68 (3) ◽  
pp. 1498-1506 ◽  
Author(s):  
Neirouz Soussi ◽  
Geneviève Milon ◽  
Jean-Hervé Colle ◽  
Evelyne Mougneau ◽  
Nicolas Glaichenhaus ◽  
...  
Keyword(s):  
T Cells ◽  
Listeria Monocytogenes ◽  
Cd4 T Cells ◽  
Leishmania Major ◽  
Ex Vivo ◽  
Experimental Models ◽  
Interleukin 4 ◽  
Cell Mediated Immunity ◽  
Th1 Cells ◽  
Ifn Γ

ABSTRACT Listeria monocytogenes has been used as an experimental live vector for the induction of CD8-mediated immune responses in various viral and tumoral experimental models. Susceptibility of BALB/c mice to Leishmania major infection has been correlated to the preferential development of Th2 CD4 T cells through an early production of interleukin 4 (IL-4) by a restricted population of CD4 T cells which react to a single parasite antigen, LACK (stands forLeishmania homologue of receptors for activated C kinase). Experimental vaccination with LACK can redirect the differentiation of CD4+ T cells towards the Th1 pathway if LACK is coadministrated with IL-12. As IL-12 is known to be induced by L. monocytogenes, we have tested the ability of a recombinant attenuated actA mutant L. monocytogenes strain expressing LACK to induce the development of LACK-specific Th1 cells in both B10.D2 and BALB/c mice, which are resistant and susceptible toL. major, respectively. After a single injection of LACK-expressing L. monocytogenes, IL-12/p40 transcripts showed a rapid burst, and peaks of gamma interferon (IFN-γ)-secreting LACK-specific Th1 cells were detected around day 5 in the spleens and livers of mice of both strains. These primed IFN-γ-secreting LACK-reactive T cells were not detected ex vivo after day 7 of immunization but could be recruited and detected 15 days later in the draining lymph node after an L. major footpad challenge. Although immunization of BALB/c mice with LACK-expressing L. monocytogenes did not change the course of the infection withL. major, immunized B10.D2 mice exhibited significantly smaller lesions than nonimmunized controls. Thus, our results demonstrate that, in addition of its recognized use for the induction of effector CD8 T cells, L. monocytogenes can also be used as a live recombinant vector to favor the development of potentially protective IFN-γ-secreting Th1 CD4 T lymphocytes.

scholarly journals Distinct Subsets of CD1d-restricted T Cells Recognize Self-antigens Loaded in Different Cellular Compartments

1999 ◽  
Vol 189 (1) ◽  
pp. 103-110 ◽  
Author(s):  
Ya-Hui Chiu ◽  
Jayanthi Jayawardena ◽  
Angela Weiss ◽  
Daniel Lee ◽  
Se-Ho Park ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
Cd4 T Cells ◽  
Cell Subset ◽  
Gene Families ◽  
T Cell Subsets ◽  
Ifn Γ ◽  
Cellular Compartments ◽  
Self Antigens

Although recent studies have indicated that the major histocompatibility complex–like, β2-microglobulin–associated CD1 molecules might function to present a novel chemical class of antigens, lipids and glycolipids, to α/β T cells, little is known about the T cell subsets that interact with CD1. A subset of CD1d-autoreactive, natural killer (NK)1.1 receptor–expressing α/β T cells has recently been identified. These cells, which include both CD4−CD8− and CD4+ T cells, preferentially use an invariant Vα14-Jα281 T cell receptor (TCR) α chain paired with a Vβ8 TCR β chain in mice, or the homologous Vα24-JαQ/Vβ11 in humans. This cell subset can explosively release key cytokines such as interleukin (IL)-4 and interferon (IFN)-γ upon TCR engagement and may regulate a variety of infectious and autoimmune conditions. Here, we report the existence of a second subset of CD1d-restricted CD4+ T cells that do not express the NK1.1 receptor or the Vα14 TCR. Like the Vα14+ NK1.1+ T cells, these T cells exhibit a high frequency of autoreactivity to CD1d, use a restricted albeit distinct set of TCR gene families, and contribute to the early burst of IL-4 and IFN-γ induced by intravenous injection of anti-CD3. However, the Vα14+ NK1.1+ and Vα14− NK1.1− T cells differ markedly in their requirements for self-antigen presentation. Antigen presentation to the Vα14+ NK1.1+ cells requires endosomal targeting of CD1d through a tail-encoded tyrosine-based motif, whereas antigen presentation to the Vα14− NK1.1− cells does not. These experiments suggest the existence of two phenotypically different subsets of CD1d-restricted T cells that survey self-antigens loaded in distinct cellular compartments.

scholarly journals Broad phenotypic alterations and potential dysfunction of lymphocytes in individuals clinically recovered from COVID-19

2021 ◽  
Author(s):  
Jingyi Yang ◽  
Maohua Zhong ◽  
Ejuan Zhang ◽  
Ke Hong ◽  
Qingyu Yang ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Cd4 T Cells ◽  
Mononuclear Cells ◽  
Cell Subset ◽  
Effector Memory ◽  
Peripheral Blood Mononuclear ◽  
Follicular Helper ◽  
Hla Dr ◽  
Ifn Γ

Abstract Although millions of patients have clinically recovered from COVID-19, little is known about the immune status of lymphocytes in these individuals. In this study, the peripheral blood mononuclear cells (PBMCs) of a clinically recovered (CR) cohort were comparatively analyzed with those of an age- and sex-matched healthy donor (HD) cohort. We found that CD8+ T cells in the CR cohort had higher numbers of effector T cells and effector memory T cells but lower Tc1 (IFN-γ+), Tc2 (IL-4+), and Tc17 (IL-17A+) cell frequencies. The CD4+ T cells of the CR cohort were decreased in frequency, especially the central memory T cell subset. Moreover, CD4+ T cells in the CR cohort showed lower PD-1 expression and had lower frequencies of Th1 (IFN-γ+), Th2 (IL-4+), Th17 (IL-17A+), and circulating follicular helper T (CXCR5+PD-1+) cells. Accordingly, the proportion of isotype-switched memory B cells (IgM−CD20hi) among B cells in the CR cohort showed a significantly lower proportion, although the level of the activation marker CD71 was elevated. For CD3−HLA-DR− lymphocytes in the CR cohort, in addition to lower levels of IFN-γ, granzyme B, and T-bet, the correlation between T-bet and IFN-γ was not observed. Additionally, by taking into account the number of days after discharge, all the phenotypes associated with reduced function did not show a tendency toward recovery within 4‒11 weeks. The remarkable phenotypic alterations in lymphocytes in the CR cohort suggest that SARS-CoV-2 infection profoundly affects lymphocytes and potentially results in dysfunction even after clinical recovery.

scholarly journals HTLV-1 bZIP factor impairs cell-mediated immunity by suppressing production of Th1 cytokines

Blood ◽  
2012 ◽  
Vol 119 (2) ◽  
pp. 434-444 ◽  
Author(s):  
Kenji Sugata ◽  
Yorifumi Satou ◽  
Jun-ichirou Yasunaga ◽  
Hideki Hara ◽  
Kouichi Ohshima ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Signaling Pathway ◽  
Cellular Immunity ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Cell Mediated Immunity ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Ifn Γ

Adult T-cell leukemia (ATL) patients and human T-cell leukemia virus-1 (HTLV-1) infected individuals succumb to opportunistic infections. Cell mediated immunity is impaired, yet the mechanism of this impairment has remained elusive. The HTLV-1 basic leucine zipper factor (HBZ) gene is encoded in the minus strand of the viral DNA and is constitutively expressed in infected cells and ATL cells. To test the hypothesis that HBZ contributes to HTLV-1–associated immunodeficiency, we challenged transgenic mice that express the HBZ gene in CD4 T cells (HBZ-Tg mice) with herpes simplex virus type 2 or Listeria monocytogenes, and evaluated cellular immunity to these pathogens. HBZ-Tg mice were more vulnerable to both infections than non-Tg mice. The acquired immune response phase was specifically suppressed, indicating that cellular immunity was impaired in HBZ-Tg mice. In particular, production of IFN-γ by CD4 T cells was suppressed in HBZ-Tg mice. HBZ suppressed transcription from the IFN-γ gene promoter in a CD4 T cell–intrinsic manner by inhibiting nuclear factor of activated T cells and the activator protein 1 signaling pathway. This study shows that HBZ inhibits CD4 T-cell responses by directly interfering with the host cell-signaling pathway, resulting in impaired cell-mediated immunity in vivo.

scholarly journals A proportion of CD4+ T cells from patients with chronic Chagas disease undergo a dysfunctional process, which is partially reversed by benznidazole treatment

2021 ◽  
Vol 15 (2) ◽  
pp. e0009059
Author(s):  
Elena Pérez-Antón ◽  
Adriana Egui ◽  
M. Carmen Thomas ◽  
Bartolomé Carrilero ◽  
Marina Simón ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chagas Disease ◽  
Granzyme B ◽  
Cell Subset ◽  
Inhibitory Receptors ◽  
Cardiac Symptoms ◽  
Before And After ◽  
Ifn Γ ◽  
Chronic Chagas Disease

Background Signs of senescence and the late stages of differentiation associated with the more severe forms of Chagas disease have been described in the Trypanosoma cruzi antigen-specific CD4+ T-cell population. However, the mechanisms involved in these functions are not fully known. To date, little is known about the possible impact of benznidazole treatment on the T. cruzi-specific functional response of CD4+ T cells. Methodology/Principal findings The functional capacity of CD4+ T cells was analyzed by cytometric assays in chronic Chagas disease patients, with indeterminate form (IND) and cardiac alterations (CCC) (25 and 15, respectively) before and after benznidazole treatment. An increase in the multifunctional capacity (expression of IFN-γ, IL-2, TNF-α, perforin and/or granzyme B) of the antigen-specific CD4+ T cells was observed in indeterminate versus cardiac patients, which was associated with the reduced coexpression of inhibitory receptors (2B4, CD160, CTLA-4, PD-1 and/or TIM-3). The functional profile of these cells shows statistically significant differences between IND and CCC (p<0.001), with a higher proportion of CD4+ T cells coexpressing 2 and 3 molecules in IND (54.4% versus 23.1% and 4.1% versus 2.4%, respectively). A significant decrease in the frequencies of CD4+ T cells that coexpress 2, 3 and 4 inhibitory receptors was observed in IND after 24–48 months of treatment (p<0.05, p<0.01 and p<0.05, respectively), which was associated with an increase in antigen-specific multifunctional activity. The IND group showed, at 9–12 months after treatment, an increase in the CD4+ T cell subset coproducing three molecules, which were mainly granzyme B+, perforin+ and IFN-γ+ (1.4% versus 4.5%). Conclusions/Significance A CD4+ T cell dysfunctional process was detected in chronic Chagas disease patients, being more exacerbated in those patients with cardiac symptoms. After short-term benznidazole treatment (9–12 months), indeterminate patients showed a significant increase in the frequency of multifunctional antigen-specific CD4+ T cells.

Perforin Expressing CD4+T Cells Respond to CMV Antigens in CMV Seropositive Patients with B Cell Chronic Lymphocytic Leukaemia (B-CLL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4787-4787
Author(s):  
James Walton ◽  
Keirissa Lawson ◽  
Maria S. Manoussaka ◽  
Amit Nathwani ◽  
Vincent Emory ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Cell Subset ◽  
Free Cell ◽  
Strong Increase ◽  
Cell Lysates ◽  
Cd69 Expression ◽  
Ifn Γ

Abstract Introduction: Perforin (PF) expressing CD4+ T cells are expanded in B-CLL patients [1] and are able to induce PF-mediated apoptosis of autologous leukaemic cells in the presence of bispecific anti-CD3/CD19 antibodies [2]. However, the role of the expanded PF+CD4+ T population in B-CLL remains unclear. In this study we have examined possible involvement of this cell subset in immune responses to cytomegalovirus (CMV). Methods: Blood mononuclear cells from 11 CMV seropositive (SP) and 6 seronegative (SN) B-CLL patients were cultured for 4 and 18 hours in presence of Downe cell lysates containing CMV-antigen or cell lysates alone (control) and brefeldin and co-stimulated with anti-CD28 and anti-CD49 monoclonal antibodies. Anti-CMV response was assessed by flow cytometry as percentages of CD69+ and IFNγ+ cells in PF+ and PF- CD4+T cell populations. Results: CD4+ T cells from 9 of 11 SP patients showed a strong increase in percentages of IFNγ+ cells after 18h, but not 4h, in culture with CMV antigens, compared to the control lysates and SN patients (Table) and healthy age-matched SP subjects (1.78±0.45, p=0.012). In contrast, none of the 6 SN patients as well as 2 out of 11 SP patients responded to CMV by increased IFNγ expression. In responders IFNγ+ cells were proportionally distributed between PF+ and PF- CD4+ T cells. High levels of cell activation measured by CD69 expression, especially in PF+ population, were mainly due to the Downe cell lysate since expression was significantly lower in lysate free cell cultures (8.3±11.5%, p=0.0018 for SP B-CLL patients). Anti-CMV response was accompanied by a decrease in percentages of CD4+PF+ cells suggesting antigen-induced degranulation. Conclusion: PF+CD4+ T cells respond to CMV antigens suggesting an expansion of mature CMV specific cytotoxic CD4+ T cells in the majority of CMV seropositive B-CLL patients. IFN-γ and CD69 expression by CD4+PF+ and PF- T cells after 18h exposure to CMV+ and CMV- lysates in CMV seropositive and seronegative B-CLL patients CD4+ PF+ CD4+ PF-CD4+ SN SP SN SP SN SP IFN- γ, % CMV+lys 0.7±0.58 9.1±7.9 2.0±3.0 p=0.013 14.4±13.6 0.61±0.56 p=0.008 9.0±8.1 CMV−lys 0.26±0.34 0.9±1.7 p=0.007 1.1±1.7 3.9±6.9 p=0.029 0.24±0.27 1.46±2.55 p=0.013 CD69+cells, % CMV+lys 16.3±14.2 21.4±13.0 41.9±35.1 51.2±30.3 14.9±13.4 20.4±13.2 CMV−lys 14.4±12.8 9.7±7.8 28.6±34.8 39.8±33.0 13.8±12.1 12.9±15.0

scholarly journals Dexmedetomidine Directs T Helper Cells toward Th1 Cell Differentiation via the STAT1-T-Bet Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Daoyun Lei ◽  
Li Liu ◽  
Songhui Xie ◽  
Haiyan Ji ◽  
Yanxing Guo ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Cd4 T Cells ◽  
Quantitative Polymerase Chain Reaction ◽  
Cell Subset ◽  
Enzyme Linked Immunosorbent Assay ◽  
T Helper ◽  
Th1 Cell ◽  
Adrenergic Antagonist ◽  
Ifn Γ

Dexmedetomidine is an α2 adrenergic receptor agonist that has been reported to modulate the polarization of CD4+ T cells. However, the underlying mechanisms by which dexmedetomidine induces T-helper 1 (Th1) cell differentiation remain poorly understood. The aim of this study was to explore the potential mechanisms through which dexmedetomidine can induce Th1 cell differentiation. Purified CD4+ T cells were stimulated with anti-CD3/anti-CD28 and then treated with dexmedetomidine. Flow cytometry analysis was adopted to measure the concentration of Th1 cells. Enzyme-linked immunosorbent assay (ELISA) and real-time quantitative polymerase chain reaction (qPCR) were performed to detect protein levels and mRNA expression, respectively, of IFN-γ and IL-4. Western blotting was used to determine the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and T-bet expression. The Th1 cell subset and IFN-γ levels were elevated in the dexmedetomidine-induced CD4+ T cells. Dexmedetomidine enhanced the phosphorylation of STAT1 and the expression of T-bet in the CD4+ T cells. Atipamezole (an α2 adrenergic antagonist) and fludarabine (a STAT1 inhibitor) reversed the dexmedetomidine-induced Th1 cell differentiation. These results suggested that dexmedetomidine induced Th1 cell differentiation via the STAT1-T-bet signaling pathway.

scholarly journals Bacterial immunotherapy for cancer induces CD4-dependent tumor-specific immunity through tumor-intrinsic interferon-γ signaling

2020 ◽  
Vol 117 (31) ◽  
pp. 18627-18637 ◽  
Author(s):  
Anthony C. Antonelli ◽  
Anna Binyamin ◽  
Tobias M. Hohl ◽  
Michael S. Glickman ◽  
Gil Redelman-Sidi
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Immune Memory ◽  
Cell Mediated Immunity ◽  
Bacterial Antigen ◽  
Specific Immunity ◽  
Enhanced Production ◽  
Bcg Therapy ◽  
Ifn Γ

Bacillus Calmette–Guérin (BCG) immunotherapy for bladder cancer is the only bacterial cancer therapy approved for clinical use. Although presumed to induce T cell-mediated immunity, whether tumor elimination depends on bacteria-specific or tumor-specific immunity is unknown. Herein we show that BCG-induced bladder tumor elimination requires CD4 and CD8 T cells, although augmentation or inhibition of bacterial antigen-specific T cell responses does not alter the efficacy of BCG-induced tumor elimination. In contrast, BCG stimulates long-term tumor-specific immunity that primarily depends on CD4 T cells. We demonstrate that BCG therapy results in enhanced effector function of tumor-specific CD4 T cells, mainly through enhanced production of IFN-γ. Accordingly, BCG-induced tumor elimination and tumor-specific immune memory require tumor cell expression of the IFN-γ receptor, but not MHC class II. Our findings establish that a bacterial immunotherapy for cancer is capable of inducing tumor immunity, an antitumor effect that results from enhanced function of tumor-specific CD4 T cells, and ultimately requires tumor-intrinsic IFN-γ signaling, via a mechanism that is distinct from other tumor immunotherapies.

scholarly journals A CD4+CD161+ T-Cell Subset Present in Unexposed Humans, Not Tb Patients, Are Fast Acting Cells That Inhibit the Growth of Intracellular Mycobacteria Involving CD161 Pathway, Perforin, and IFN-γ/Autophagy

2021 ◽  
Vol 12 ◽  
Author(s):  
Rui Yang ◽  
Ying Peng ◽  
Jiang Pi ◽  
Yidian Liu ◽  
Enzhuo Yang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Protective Immunity ◽  
Cell Subset ◽  
A549 Cells ◽  
T Cell Subset ◽  
Ifn Γ ◽  
Mycobacterial Growth ◽  
Fast Acting

It remains undefined whether a subset of CD4+ T cells can function as fast-acting cells to control Mycobacterium tuberculosis (Mtb) infection. Here we show that the primary CD4+CD161+ T-cell subset, not CD4+CD161-, in unexposed healthy humans fast acted as unconventional T cells capable of inhibiting intracellular Mtb and BCG growth upon exposure to infected autologous and allogeneic macrophages or lung epithelial A549 cells. Such inhibition coincided with the ability of primary CD4+CD161+ T cells to rapidly express/secrete anti-TB cytokines including IFN-γ, TNF-α, IL-17, and perforin upon exposure to Mtb. Mechanistically, blockades of CD161 pathway, perforin or IFN-γ by blocking mAbs abrogated the ability of CD4+CD161+ T cells to inhibit intracellular mycobacterial growth. Pre-treatment of infected macrophages with inhibitors of autophagy also blocked the CD4+CD161+ T cell-mediated growth inhibition of mycobacteria. Furthermore, adoptive transfer of human CD4+CD161+ T cells conferred protective immunity against mycobacterial infection in SCID mice. Surprisingly, CD4+CD161+ T cells in TB patients exhibited a loss or reduction of their capabilities to produce perforin/IFN-γ and to inhibit intracellular growth of mycobacteria in infected macrophages. These immune dysfunctions were consistent with PD1/Tim3 up-regulation on CD4+CD161+ T cells in active tuberculosis patients, and the blockade of PD1/Tim3 on this subset cells enhanced the inhibition of intracellular mycobacteria survival. Thus, these findings suggest that a fast-acting primary CD4+CD161+T-cell subset in unexposed humans employs the CD161 pathway, perforin, and IFN-γ/autophagy to inhibit the growth of intracellular mycobacteria, thereby distinguishing them from the slow adaptive responses of conventional CD4+ T cells. The presence of fast-acting CD4+CD161+ T-cell that inhibit mycobacterial growth in unexposed humans but not TB patients also implicates the role of these cells in protective immunity against initial Mtb infection.

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