Abstract
The T cell co-receptor CD8αβ enhances T cell sensitivity to antigen, however studies indicate CD8αα has the converse effect and acts as a co-repressor. Using a combination of Thymic Leukemia (TL) antigen tetramer, which directly binds CD8αα, anti-CD161, and anti-Vα7.2 antibodies we have been able for the first time to clearly define CD8αα expression on human CD8 T cells subsets. In healthy controls CD8αα is most highly expressed by CD161 “bright” (CD161++) mucosal associated invariant T (MAIT) cells, with CD8αα expression highly restricted to the TCR Vα7.2+ cells of this subset. We also identified CD8αα-expressing populations within the CD161 “mid” (CD161+) and “negative” (CD161−) non-MAIT CD8 T cell subsets and show TL-tetramer binding to correlate with expression of CD8β at low levels in the context of maintained CD8α expression (CD8α+CD8βlow). In addition, we found CD161−CD8α+CD8βlow 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 CD8αα expressing T cells are an effector-memory population (CD45RA−, CCR7−, CD62L−) that express markers of activation and maturation (HLA-DR+, CD28−, CD27−, CD57+) and are functionally distinct, expressing greater levels of TNF-α and IFN-γ on stimulation and perforin at rest than their CD8α+CD8βhigh counterparts. Antigen-specific T cells in HLA-B∗4201+HIV-1 infected patients are found within both the CD161−CD8α+CD8βhigh and CD161−CD8α+CD8βlow populations. Overall we have clearly defined CD8αα expressing human T cell subsets using the TL-tetramer, and have demonstrated CD161−CD8α+CD8βlow populations, highly expanded in disease settings, to co-express CD8αβ and CD8αα. Co-expression of CD8αα on CD8αβ T cells may impact on their overall function in vivo and contribute to the distinctive phenotype of highly differentiated populations in HBV and HIV-1 infection.
Highlights
CD8α is a cell surface glycoprotein that can be expressed either as a disulfide-linked heterodimer together with CD8β or as a homodimer
DEFINING CD8β EXPRESSION LEVELS BY CD161++, CD161+, AND CD161− CD8α+ T CELL SUBSETS We first addressed the distribution of CD8β staining in peripheral blood; since we have previously shown a substantial impact of CD161 expression on this, we analyzed the CD161++, CD161+, and CD161− T cell populations in parallel
The SP CD8αα (CD8α+CD8βneg) population is exclusive to the CD161++ mucosal associated invariant T (MAIT) cell population as demonstrated previously [5] and in the healthy controls (HC) shown (Figure 1B)
Summary
CD8α is a cell surface glycoprotein that can be expressed either as a disulfide-linked heterodimer together with CD8β or as a homodimer. In contrast to CD8αβ, CD8αα is never expressed on naïve T cells but readily induced on strongly activated T cells [1]. CD8αα can be expressed on double negative or CD4+ or CD8αβ+ CD3+ TCRαβ+ T cells whereas CD3+ TCRγδ+ T cells and NK cells express mostly CD8αα alone [2]. CD8αα-expressing populations are the predominant intraepithelial lymphocyte subset of the small bowel and either TCR γδ+ or αβ+ [3]. CD8αα has been identified as a marker of murine memory CD8αβ TCRαβ+ cells, with affinity induced expression in early T cell responses identifying a memory precursor population in both an LCMV [4] and Listeria model [1]. We have recently shown single-positive (SP) CD8αα
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