CD8 alpha alpha expression marks terminally differentiated human CD8+T cells expanded in chronic viral infection

The T cell co-receptor CD8 alpha beta enhances T cell sensitivity to antigen, however studies indicate CD8 alpha alpha has the converse effect and acts as a co-repressor. Using a combination of Thymic Leukemia (TL) antigen tetramer, which directly binds CD8aa, anti-CD161, and anti-V alpha 7.2 antibodies we have been able for the first time to clearly define CD8aa expression on human CD8T cells subsets. In healthy controls CD8aa is most highly expressed by CD161 bright (CD161++) mucosal associated invariant T (MAIT) cells, with CD8aa expression highly restricted to the TCRV alpha 7.2+ cells of this subset. We also identified CD8 alpha alpha-expressing populations within the CD161 mid (CD161+) and negative (CD161) non-MAIT CD8 T cell subsets and show Thtetramer binding to correlate with expression of CD8 beta at low levels in the context of maintained CD8 alpha expression (CD8 alpha+CD8 beta(low)). In addition, we found CD161-CD8 alpha+CD8 beta(low) populations to be significantly expanded in the peripheral blood of HIV-1 and hepatitis B (mean of 47 and 40% of CD161 T cells respectively) infected individuals. Such CD8aa expressing T cells are an effector-memory population (CD45RA-, CCR7-, CD62L-) that express markers of activation and maturation (HLADR+, CD28-, CD27-, CD57+) and are functionally distinct, expressing greater levels of TNF-alpha and IFN-gamma on stimulation and perforin at rest than their CD8 alpha+CD8 beta(high) counterparts. Antigen-specific T cells in HLA-B*4201+HIV-1 infected patients are found within both the CD161 CD8 alpha+CD8 beta(high) and CD161-CD8 alpha+CD8 beta(low) populations. Overall we have clearly defined CD8aa expressing human T cell subsets using the Thtetramer, and have demonstrated CD161 CD8a+CD8130w populations, highly expanded in disease settings, to co-express CD8 alpha beta and CD8 alpha alpha. Co-expression of CD8 alpha alpha on CD alpha beta T cells mayimpact on their overall function in vivo and contribute to the distinctive phenotype of highly differentiated populations in HBV and HIV-1 infection.