NKG2C/E Marks the Unique Cytotoxic CD4 T Cell Subset, ThCTL, Generated by Influenza Infection

Marshall, Nikki B.; Vong, Allen M.; Devarajan, Priyadharshini; Brauner, Matthew; Kuang, Yi; Nayar, Ribhu; Schutten, Elizabeth; Castonguay, Catherine; Berg, Leslie J.; Nutt, Stephen L.; Swain, Susan L.

doi:10.4049/jimmunol.1601297

Cited by 56 publications

(75 citation statements)

References 78 publications

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“…In addition to confirming previous observations of degranulation , we found evidence of intracellular storage of granzyme B and observed antigen‐specific cytotoxic activity, both highlighting a direct effector role of CD4 T cells in the control of HHV‐6B, as previously suggested . In other models, it has been observed that CD4 T cells may act as effector cells exerting cytotoxic activities . As previously observed , we found that infection of SupT1.CIITA cells with HHV‐6B resulted in downregulation of MHC‐class I.…”

Section: Discussionsupporting

confidence: 92%

Naturally processed HLA‐DR3‐restricted HHV‐6B peptides are recognized broadly with polyfunctional and cytotoxic CD4 T‐cell responses

et al. 2019

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Human herpes virus 6B (HHV‐6B) is a widespread virus that infects most people early in infancy and establishes a chronic life‐long infection with periodic reactivation. CD4 T cells have been implicated in control of HHV‐6B, but antigenic targets and functional characteristics of the CD4 T‐cell response are poorly understood. We identified 25 naturally processed MHC‐II peptides, derived from six different HHV‐6B proteins, and showed that they were recognized by CD4 T‐cell responses in HLA‐matched donors. The peptides were identified by mass spectrometry after elution from HLA‐DR molecules isolated from HHV‐6B‐infected T cells. The peptides showed strong binding to matched HLA alleles and elicited recall T‐cell responses in vitro. T‐cell lines expanded in vitro were used for functional characterization of the response. Responding cells were mainly CD3+CD4+, produced IFN‐γ, TNF‐α, and low levels of IL‐2, alone or in combination, highlighting the presence of polyfunctional T cells in the overall response. Many of the responding cells mobilized CD107a, stored granzyme B, and mediated specific killing of peptide‐pulsed target cells. These results highlight a potential role for polyfunctional cytotoxic CD4 T cells in the long‐term control of HHV‐6B infection.

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Section: Discussionsupporting

confidence: 92%

Naturally processed HLA‐DR3‐restricted HHV‐6B peptides are recognized broadly with polyfunctional and cytotoxic CD4 T‐cell responses

et al. 2019

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“…CD4 cytotoxic T helper cells (ThCTL) have been shown to be an important effector population generated in the tissue during IAV immune responses (57, 59, 60). Generation of ThCTL depend on IL-2, but in vitro development of cytotoxicity is not IL-6 dependent (57), though in vivo requirements for IL-6 in ThCTL generation are not known.…”

Section: Resultsmentioning

confidence: 99%

IL-6 Production by TLR-Activated APC Broadly Enhances Aged Cognate CD4 Helper and B Cell Antibody Responses In Vivo

Brahmakshatriya

Kuang

Devarajan

et al. 2017

The Journal of Immunology

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Naive CD4 T cell responses, especially their ability to help B cell responses, become compromised with aging. We find that using APC pre-treated ex vivo with TLR agonists, polyI:C and CpG, to prime naive CD4 T cells in vivo, restores their ability to expand and become germinal center T follicular helpers and enhances B cell IgG antibody production. Enhanced helper responses are dependent on IL-6 production by the activated APC. Aged naive CD4 T cells respond sub-optimally to IL-6 compared to the young, such that higher doses are required to induce comparable signaling. Pre-activating APC overcomes this deficiency. Responses of young CD4 T cells are also enhanced by pre-activating APC with similar effects but with only partial IL-6 dependency. Strikingly, introducing just the activated APC into aged mice significantly enhances otherwise compromised antibody production to inactivated influenza vaccine. These findings reveal a central role for production of IL-6 by APC during initial cognate interactions in the generation of effective CD4 T cell help, which becomes greater with age. Without APC activation aging CD4 T cell responses shift towards IL-6-independent Th1 and ThCTL responses. Thus, strategies that specifically activate and provide antigen to APC could potentially enhance Ab mediated protection in vaccine responses.

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“…However, it is also possible that CD4 þ CTLs may comprise a distinct, independent subset of CD4 þ effector T cells that differ from conventional Th1 cells (10). Indeed, several recent reports have identified specific markers for CD4 þ CTLs (11)(12)(13)(14). Interestingly, Eomes is expressed in many of the cells expressing these markers, as well as in other CD4 þ T cells with cytolytic properties (15)(16)(17)(18); these findings suggested that Eomes governs development of CD4 þ CTLs and that Eomes expression is a marker for CD4 þ CTLs.…”

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confidence: 99%

Role of T‐bet, the master regulator of Th1 cells, in the cytotoxicity of murine CD4⁺ T cells

Eshima

Misawa

Ohashi

et al. 2018

Microbiology and Immunology

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Although CD4 T cells are generally regarded as helper T cells, some activated CD4 T cells have cytotoxic properties. Given that CD4 cytotoxic T lymphocytes (CTLs) often secrete IFN-γ, CTL activity among CD4 T cells may be attributable to Th1 cells, where a T-box family molecule, T-bet serves as the "master regulator". However, although the essential contribution of T-bet to expression of IFN-γ has been well-documented, it remains unclear whether T-bet is involved in CD4 T cell-mediated cytotoxicity. In this study, to investigate the ability of T-bet to confer cytolytic activity on CD4 T cells, the T-bet gene (Tbx21) was introduced into non-cytocidal CD4 T cell lines and their cytolytic function analyzed. Up-regulation of FasL (CD178), which provided the transfectant with cytotoxicity, was observed in Tbx21transfected CD4 T cells but not in untransfected parental cells. In one cell line, T-bet transduction also induced perforin gene (Prf1) expression and Tbx21 transfectants efficiently killed Fas target cells. Although T-bet was found to repress up-regulation of CD40L (CD154), which controls FasL-mediated cytolysis, the extent of CD40L up-regulation on in vitro-differentiated Th1 cells was similar to that on Th2 cells, suggesting the existence of a compensatory mechanism. These results collectively indicate that T-bet may be involved in the expression of genes, such as FasL and Prf1, which confer cytotoxicity on Th1 cells.

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NKG2C/E Marks the Unique Cytotoxic CD4 T Cell Subset, ThCTL, Generated by Influenza Infection

Cited by 56 publications

References 78 publications

Naturally processed HLA‐DR3‐restricted HHV‐6B peptides are recognized broadly with polyfunctional and cytotoxic CD4 T‐cell responses

Naturally processed HLA‐DR3‐restricted HHV‐6B peptides are recognized broadly with polyfunctional and cytotoxic CD4 T‐cell responses

IL-6 Production by TLR-Activated APC Broadly Enhances Aged Cognate CD4 Helper and B Cell Antibody Responses In Vivo

Role of T‐bet, the master regulator of Th1 cells, in the cytotoxicity of murine CD4⁺ T cells

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NKG2C/E Marks the Unique Cytotoxic CD4 T Cell Subset, ThCTL, Generated by Influenza Infection

Cited by 56 publications

References 78 publications

Naturally processed HLA‐DR3‐restricted HHV‐6B peptides are recognized broadly with polyfunctional and cytotoxic CD4 T‐cell responses

Naturally processed HLA‐DR3‐restricted HHV‐6B peptides are recognized broadly with polyfunctional and cytotoxic CD4 T‐cell responses

IL-6 Production by TLR-Activated APC Broadly Enhances Aged Cognate CD4 Helper and B Cell Antibody Responses In Vivo

Role of T‐bet, the master regulator of Th1 cells, in the cytotoxicity of murine CD4+ T cells

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Role of T‐bet, the master regulator of Th1 cells, in the cytotoxicity of murine CD4⁺ T cells