Program for memory differentiation is CD8 T cell intrinsic and not determined by CD4 help. (IRC10P.467)

To elucidate the fundamental role of CD4 help in CD8 T cell response, the dynamics of the CD8 T cells participating in the help-deficient response was tracked longitudinally via in vivo imaging and phenotypic analyses. Help-deficient CD8 T cells underwent intact effector differentiation with fast kinetics, albeit insignificant burst expansion. However, they failed to effectively eliminate the antigen, which rendered them to be activated continuously, defective in memory cell differentiation, and exhausted eventually. Although PD-1-deficiency rescued the exhaustion, it could not restore the memory differentiation. Instead, simply increasing the numbers of effector CD8 T cells or accelerating antigen clearance enabled efficient memory generation even in the absence of help. These results demonstrate that memory program is intrinsic to CD8 T cells, not encoded by CD4 help, and provide insight into the role of CD4 help, permitting a better understanding of CD8 T cell differentiation and immunity.