THE LEVEL OF CD4 SURFACE PROTEIN INFLUENCES T-CELL SELECTION IN THE THYMUS

During T cell development thymocytes are subjected to positive and neg ative selection criteria to ensure that the mature T cell repertoire i s MHC restricted, yet self tolerant at the same time, The CD4 and CD8 coreceptors are thought to play a crucial role in this developmental p rocess, To elucidate the role of CD4 in T cell selection, we have prod uced a mouse strain that expresses CD4 at a reduced level, We used hom ologous recombination in embryonic stem cells to insert neo into the 3 ' untranslated region of CD4, The resulting mice have a reduction in t he percentage of CD4(+) cells in the thymus and a concomitant increase in CD8(+) cells, In addition, breeding two individual class Ii-restri cted TCR transgenic mice onto the CD4(low) (low level of CD4) mutant b ackground affects the selection of each TCR differentially. In one cas e (AND TCR transgenic), significantly fewer CD4(+) cells with the tran sgenic TCR develop on the CD4(low) mutant background, whereas in the o ther (5C.C7 TCR transgenic), selection to the CD4 lineage is only slig htly reduced, These data support the differential avidity model of pos itive and negative selection, With little or no avidity, the cell succ umbs to programmed cell death, low to moderate avidity leads to positi ve selection, and an avidity above a certain threshold, presumably abo ve one that would lead to autoreactivity in the periphery, results in clonal deletion, These data also support the idea that a minimum avidi ty threshold for selection exists and that CD4 plays a crucial role in determining this avidity.