Wednesday, February 24, 2016

Deceptive strength applies to T cells as well

This week journal Nature Immunology published interesting study examining the correlation between TCR affinity and T cell competence. Using M. tuberculosis infection model, the authors showed that strength of antigen recognition by TCR reduces T cell competence long-term.

For this study the authors compared control of M. tuberculosis infection by two T cell receptor (TCR) transgenic mouse, named C24 and C7. In C24, CD4+ T cells express a TCR with high avidity [affinity, here] for M. tuberculosis antigen ESAT6, while in C7, CD4+ T cells express a TCR with intermediate avidity for ESAT6. Surprisingly, adoptive transfer of in vitro generated TH1 cells from high avidity C24 mice provided significantly less protection against lung M. tuberculosis infection compared to Th1 cells from intermediate avidity C7 mice.
Interestingly, C24 Th1 cells showed more significant down-regulation of surface TCR post-transfer in both infected and un-infected hosts [it appears that in vitro activated Th1 continue to proliferate independent of antigen].

In addition, while TCR down-regulation was a general feature of activated CD4+ T cells (including endogenous, non-transgenic ESAT6-specific T cells), such TCR down-regulation was profound and long-term for C24 T cells.

Importantly, unlike C7, C24 Th1 cells transferred to uninfected hosts and harvested at day 13 showed drastic reduction of antigen-specific cytokine production.

Moreover, mice transferred with naive C24 T cells and infected with L. monocytogenes–ESAT6 and reinfected 1 month later showed failure to mount secondary response.

In summary, this study revealed that high avidity (affinity) T cells do not necessarily represent the best T cells to control infection. We could extrapolate this observation to include T cells with high affinity TCR against tumor-specific antigens. Important consideration in designing TCR transduced T cells for adoptive T cell immunotherapy.

David Usharauli

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