Endogenous IL-33 enhances Th2 cytokine production and T-cell responses during allergic airway inflammation

AbstractMaintaining and limiting T cell responses to constant antigen stimulation is critical to control pathogens and maintain self-tolerance, respectively. Antigen recognition by T cell receptors (TCRs) induces signalling that activates T cells to produce cytokines and also leads to the downregulation of surface TCRs. In other systems, receptor downregulation can induce perfect adaptation to constant stimulation by a mechanism known as state-dependent inactivation that requires complete downregulation of the receptor or the ligand. However, this is not the case for the TCR, and therefore, precisely how TCR downregulation maintains or limits T cell responses is controversial. Here, we observed that in vitro expanded primary human T cells exhibit perfect adaptation in cytokine production to constant antigen stimulation across a 100,000-fold variation in affinity with partial TCR downregulation. By directly fitting a mechanistic model to the data, we show that TCR downregulation produces imperfect adaptation, but when coupled to a switch produces perfect adaptation in cytokine production. A pre-diction of the model is that pMHC-induced TCR signalling continues after adaptation and this is confirmed by showing that, while costimulation cannot prevent adaptation, CD28 and 4-1BB signalling reactivated adapted T cells to produce cytokines in a pMHC-dependent manner. We show that adaptation also applied to 1st generation chimeric antigen receptor (CAR)-T cells but is partially avoided in 2nd generation CARs. These findings high-light that even partial TCR downregulation can limit T cell responses by producing perfect adaptation rendering T cells dependent on costimulation for sustained responses.

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Monitoring HIV-specific CD8+ T cell responses by intracellular cytokine production

Immunology Letters ◽

10.1016/s0165-2478(01)00273-5 ◽

2001 ◽

Vol 79 (1-2) ◽

pp. 117-125 ◽

Cited By ~ 47

Author(s):

Michael R Betts ◽

Joseph P Casazza ◽

Richard A Koup

Keyword(s):

T Cell ◽

Cytokine Production ◽

T Cell Responses ◽

Cd8 T Cell ◽

Intracellular Cytokine ◽

Cell Responses

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Mast Cells Modulate Antigen-Specific CD8+ T Cell Activation During LCMV Infection

Frontiers in Immunology ◽

10.3389/fimmu.2021.688347 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yana Hackler ◽

Frank Siebenhaar ◽

Max Löhning ◽

Marcus Maurer ◽

Melba Muñoz

Keyword(s):

T Cells ◽

T Cell ◽

Mast Cells ◽

Immune Responses ◽

Cytokine Production ◽

T Cell Responses ◽

Type I ◽

Cell Responses ◽

Deficient Mice ◽

Lcmv Infection

Mast cells (MCs), strategically localized at mucosal surfaces, provide first-line defense against pathogens and shape innate and adaptive immune responses. Recent studies have shown that MCs are involved in pathogenic responses to several viruses including herpes simplex viruses, dengue virus, vaccinia virus and influenza virus. However, the underlying mechanisms of MCs in the activation of CD8+ T cells during viral infections are not fully understood. Therefore, we investigate the role of MCs in the development of virus-specific CD8+ T cell responses using the well-characterized murine lymphocytic choriomeningitis virus (LCMV) model and the transgenic MasTRECK mice that contain the human diphtheria toxin receptor as an inducible MC-deficient model. Here, we report that MCs are essential for the activation and expansion of virus-specific CD8+ T cells. After MC depletion and subsequent intradermal LCMV infection, the CD8+ T cell effector phenotype and antiviral cytokine production were impaired at the peak of infection (day 8 p.i.). Importantly, MC-deficient mice were unable to control the infection and exhibited significantly higher viral loads in the spleen and in the ear draining lymph nodes compared to that of wild type control mice. In the absence of MCs, dendritic cell (DC) activation was impaired upon LCMV infection. In addition, type-I interferon (IFN) levels in the serum and in the spleen of MC-deficient mice were reduced during the first days of infection. Interestingly, depletion of MCs after intradermal LCMV infection did not impair virus-specific CD8+ T cell expansion, activation or antiviral cytokine production. In summary, our results indicate that MCs play a pivotal role in the activation and antiviral functions of CD8+ T cells through proper DC activation. A better understanding of the impact of MCs on CD8+ T cell responses is mandatory to improve antiviral immune responses.

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