The CD8 isoform CD8alphaalpha is not a functional homologue of the TCR co-receptor CD8alphabeta.

Although structurally similar, CD8alphabeta and CD8alphaalpha have notably diverted with regard to function. Whereas CD8alphabeta functions as a T-cell receptor (TCR) co-receptor on MHC-class-I-restricted thymocytes and mature T cells, CD8alphaalpha is unable to support conventional positive selection, and can be expressed on T cells independent of the MHC restriction of their TCR. CD8alphaalpha induction is consistent with antigenic stimulation through the TCR, and recent developments have now shown that CD8alphaalpha induced on agonist-triggered immature thymocytes, antigenic-stimulated conventional CD8alphabeta T cells and mucosal T cells mediates the specific modulation of TCR activation signals to facilitate their survival and differentiation into various specialized T-cell subsets.