CD8 REQUIREMENTS FOR NEGATIVE SELECTION EVENTS ARE DIRECTLY RELATED TO THE TCR-ANTIGEN INTERACTION

Positive selection of class I-restricted T cells has been suggested to always require the surface expression of CD8 molecules on CD4(+)8(+) thymocytes, whilst negative selection was found to be differentially d ependent, relating to the antigen being engaged by the T cell receptor (TCR). We have studied the CD8-dependency of positive and negative se lection using two TCR-transgenic (Tg) mice models, which both react ag ainst the same allo-antigen, H-2K(b), back crossed with mice which are deficient for the expression of CD8. Whilst CD8 expression was always required for positive selection of cells expressing high levels of th e Tg-TCR, events of negative selection were differentially dependent u pon CD8, reflecting the CD8-dependency of the original CTL clones. For one TCR-Tg model (derived from a CD8-dependent CTL clone), deletion o f CD4(+)8(+) thymocytes was partially dependent upon the expression of CD8, though there was still selection against Tg-TCR positive CD4(+) cells, which normally exit to the periphery expressing low levels of T g-TCR. For the other model (derived from a CD8-independent CTL clone) negative selection was unaffected by the absence of CD8. For both mode ls the CD4(-)8(-) Tg-TCR positive population was unaffected by the abs ence of CD8, including, for the CD8-independent model, reduced express ion of the Tg-TCR/CD3 complex. These results suggest that CD8 expressi on may be a prerequisite for positive selection, whilst negative selec tion events can occur in the absence of CD8, depending directly upon t he TCR-antigen interaction.