Differential Regulation of Antigen-Specific CD8+ T Cell Responses by IL-12p40 in a Dose-Dependent Manner

Influenza infections induce a rapid, but transient, dendritic cell (DC) migration from the lungs to the lymph nodes (LNs) that is followed by substantial recruitment of DCs into the lungs without subsequent migration to the LNs. Given that peripheral DCs are primarily thought to be involved in the initiation of adaptive immunity after migration into lymphoid tissues, what role these newly lung-recruited DCs play in influenza virus immunity is unclear. In this study, we demonstrate that loss of non-LN migratory pulmonary DC subsets increases mortality, sustains higher viral titers, and impairs pulmonary CD8 T cell responses. Reconstitution of the lungs with pulmonary plasmacytoid DCs, CD8α+ DCs, or interstitial DCs restores CD8 T cell responses in a cell contact–, major histocompatability complex I–, and influenza peptide–dependent manner. Thus, after their initial activation in the LN, protective influenza-specific CD8 T cell responses require additional antigen-dependent interactions, specifically with DCs in the lungs.

Download Full-text

IL-27 promotes the expansion of self-renewing CD8+ T cells in persistent viral infection

Journal of Experimental Medicine ◽

10.1084/jem.20190173 ◽

2019 ◽

Vol 216 (8) ◽

pp. 1791-1808 ◽

Cited By ~ 3

Author(s):

Zhe Huang ◽

Jaroslav Zak ◽

Isaraphorn Pratumchai ◽

Namir Shaabani ◽

Vincent F. Vartabedian ◽

...

Keyword(s):

T Cells ◽

Cell Division ◽

T Cell ◽

Cd8 T Cells ◽

T Cell Responses ◽

Cd8 T Cell ◽

Dependent Manner ◽

Chronic Infections ◽

Cell Responses ◽

Dividing Cells

Chronic infection and cancer are associated with suppressed T cell responses in the presence of cognate antigen. Recent work identified memory-like CXCR5+ TCF1+ CD8+ T cells that sustain T cell responses during persistent infection and proliferate upon anti-PD1 treatment. Approaches to expand these cells are sought. We show that blockade of interferon type 1 (IFN-I) receptor leads to CXCR5+ CD8+ T cell expansion in an IL-27– and STAT1-dependent manner. IFNAR1 blockade promoted accelerated cell division and retention of TCF1 in virus-specific CD8+ T cells. We found that CD8+ T cell–intrinsic IL-27 signaling safeguards the ability of TCF1hi cells to maintain proliferation and avoid terminal differentiation or programmed cell death. Mechanistically, IL-27 endowed rapidly dividing cells with IRF1, a transcription factor that was required for sustained division in a cell-intrinsic manner. These findings reveal that IL-27 opposes IFN-I to uncouple effector differentiation from cell division and suggest that IL-27 signaling could be exploited to augment self-renewing T cells in chronic infections and cancer.

Download Full-text

Zoledronic acid induces dose-dependent increase of antigen-specific CD8 T-cell responses in combination with peptide/poly-IC vaccine

Vaccine ◽

10.1016/j.vaccine.2016.01.026 ◽

2016 ◽

Vol 34 (10) ◽

pp. 1275-1281 ◽

Cited By ~ 1

Author(s):

Hye-Mi Park ◽

Hyun-Il Cho ◽

Chang-Ae Shin ◽

Hyun-Jung Shon ◽

Tai-Gyu Kim

Keyword(s):

T Cell ◽

Zoledronic Acid ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cell Responses ◽

Dose Dependent Increase ◽

Dose Dependent

Download Full-text

Differential Regulation of Simultaneous Antitumor and Alloreactive CD8+ T-Cell Responses in the Same Host by Rapamycin

American Journal of Transplantation ◽

10.1111/j.1600-6143.2011.03811.x ◽

2011 ◽

Vol 12 (1) ◽

pp. 233-239 ◽

Cited By ~ 6

Author(s):

S. Maleki Vareki ◽

M. J. Harding ◽

J. Waithman ◽

D. Zanker ◽

A. N. Shivji ◽

...

Keyword(s):

T Cell ◽

T Cell Responses ◽

Cd8 T Cell ◽

Differential Regulation ◽

Cell Responses

Download Full-text

CD8 T cells drive anorexia, dysbiosis, and blooms of a commensal with immunosuppressive potential after viral infection

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2003656117 ◽

2020 ◽

Vol 117 (40) ◽

pp. 24998-25007

Author(s):

Lara Labarta-Bajo ◽

Anna Gramalla-Schmitz ◽

Romana R. Gerner ◽

Katelynn R. Kazane ◽

Gregory Humphrey ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Immune Cell ◽

T Cell Responses ◽

Cd8 T Cell ◽

Intestinal Microbiome ◽

Dependent Manner ◽

Cell Responses ◽

Fast Spreading

Infections elicit immune adaptations to enable pathogen resistance and/or tolerance and are associated with compositional shifts of the intestinal microbiome. However, a comprehensive understanding of how infections with pathogens that exhibit distinct capability to spread and/or persist differentially change the microbiome, the underlying mechanisms, and the relative contribution of individual commensal species to immune cell adaptations is still lacking. Here, we discovered that mouse infection with a fast-spreading and persistent (but not a slow-spreading acute) isolate of lymphocytic choriomeningitis virus induced large-scale microbiome shifts characterized by increased Verrucomicrobia and reduced Firmicute/Bacteroidetes ratio. Remarkably, the most profound microbiome changes occurred transiently after infection with the fast-spreading persistent isolate, were uncoupled from sustained viral loads, and were instead largely caused by CD8 T cell responses and/or CD8 T cell-induced anorexia. Among the taxa enriched by infection with the fast-spreading virus, Akkermansia muciniphila, broadly regarded as a beneficial commensal, bloomed upon starvation and in a CD8 T cell-dependent manner. Strikingly, oral administration of A. muciniphila suppressed selected effector features of CD8 T cells in the context of both infections. Our findings define unique microbiome differences after chronic versus acute viral infections and identify CD8 T cell responses and downstream anorexia as driver mechanisms of microbial dysbiosis after infection with a fast-spreading virus. Our data also highlight potential context-dependent effects of probiotics and suggest a model in which changes in host behavior and downstream microbiome dysbiosis may constitute a previously unrecognized negative feedback loop that contributes to CD8 T cell adaptations after infections with fast-spreading and/or persistent pathogens.

Download Full-text