Differential regulation of antiviral T-cell immunity results in stable CD8+ but declining CD4+ T-cell memory

Emerging evidence indicates that CD8(+) and CD4(+) T-cell immunity is differentially regulated. Here we have delineated differences and commonalities among antiviral T-cell responses by enumeration and functional profiling of eight specific CD8(+) and CD4(+) T-cell populations during primary, memory and recall responses. A high degree of coordinate regulation among all specific T-cell populations stood out against an approximately 20-fold lower peak expansion and prolonged contraction phase of specific CD4(+) T-cell populations. Surprisingly, although CD8(+) T-cell memory was stably maintained for life, levels of specific CD4(+) memory T cells gradually declined. However, this decay, which seemed to result from less efficient rescue from apoptosis, did not affect functionality of surviving virus-specific CD4(+) T cells. Our results indicate that CD4(+) T-cell memory might become limiting under physiological conditions and that conditions precipitating CD4(+) T-cell loss might compromise protective immunity even in the presence of unimpaired CD8+ T-cell responses.