Enigma of the peripheral tolerance: CTLA4+ anergic CD8 T cells

When Sir Burnet first proposed clonal-selection theory of everything to explain how immune system could detect non-self antigens while at the same time avoiding autoimmunity, he probably had no idea that his theory would require major and multiple modifications to accommodate new data.

This new study from journal Science is another piece in the puzzle. This work, led by Shimon Sakaguchi at Osaka University, studied self-reactive CD8 T cells from the healthy humans or from vitiligo patients's blood.

The authors studied self-antigen, melanin-specific CD8 T cells. In T cell proliferation assay, Melan-A specific CD8 T cells, almost undetectable before stimulation, undergo robust, multiple-round proliferation and expand to sizable population. However, in presence of regulatory T cells, Melan-A specific CD8 T cells undergo single-round, abortive proliferation.

Tetramer staining indicated that in presence of regulatory T cells, Melan-A specific CD8 T cells mostly consisted of low-affinity clones and displayed anergic phenotype with low cytokine expression (however, please note that small population of CD8 T cells displayed high affinity binding to tetramers even in presence of regulatory T cells. This suggest to me that regulatory T cells suppress proliferation of these high-affinity Melan-A specific CD8 T cells).

Surface staining showed that anergic CD8 T cells generated in presence of T regs express high levels of CTLA-4 and CCR7.

Direct ex vivo analysis of healthy human CD8 T cells showed that naive CD8 T cells consisted of CTLA4+ and CTLA4- population. Antigen-specific or non-specific stimulation of these two population showed that CTLA4+ naive CD8 T cells were (1) enriched in self-specific CD8 T cells, (2) displayed anergic phenotype (abortive proliferation) and (3) preferentially undergo apoptosis in mixed culture.

In summary, the authors showed that healthy human blood contains two types of "naive" CD8 T cell populations: naive, CTLA4neg functionally-competent CD8 T cells and anergic, CTLA4pos functionally-impaired CD8 T cell population.

It appears, though there is no direct evidence, that T regs control self-antigen specific CTLA4+ anergic CD8 T cell development from high-affinity clones. If the model is accurate, then it is not clear why healthy human blood still contains high affinity, self-antigen specific CTLA4- CD8 T cell population (see Fig. 1b tetramer staining. I wonder whether small population of high-affinity CD8 T cells in Treg culture express CTLA4). 

David Usharauli