CD4 T cells guarantee optimal competitive fitness of CD8 memory T cells

Abstract

We studied the contribution of CD4 T cell help to survival and competitive fitness of CD8 memory T cells specific for influenza virus nucleoprotein. In agreement with recent studies, the optimal generation of functional memory CD8 T cells required CD4 help, although longterm maintenance of resting CD8 memory T cells did not absolutely depend on the presence of CD4 T cells. Nonetheless, CD4 T cells were essential during differentiation of CD8 memory T cells to imprint on them the capacity to compete effectively with other memory T cells. CD8 memory cells generated with help survived better in secondary polyclonal hosts, and co-transfer into lymphopenic hosts together with "un-helped" CD8 memory cells showed improved homeostatic expansion of CD8 memory cells that had been generated with CD4 help. Therefore, the requirement for CD4 help in CD8 T cell memory extends to homeostatic parameters that ensure the maintenance and competitive fitness of memory clones.

Effector and Memory CD8+ T Cells Can Be Generated in Response to Alloantigen Independently of CD4+ T Cell Help

“…Therefore, homeostatic proliferation appears to have little or no role in T cell priming, graft rejection, and memory T cell generation, although more subtle effects cannot be entirely excluded. However, the absence of other memory T cell clones in these experiments may have contributed to the survival of memory BM3 T cells, as Johansen et al (17) have suggested that the presence of CD4 ϩ T cells during CD8 ϩ T cell priming enhances the competitive fitness of memory CD8 ϩ T cells. Taken together we feel these data expand current knowledge of the role of CD4 ϩ T cells in the generation and survival of effector and memory CD8 ϩ T cells and provide support for the concept that under certain conditions, memory CD8 ϩ T cells can develop in the absence of CD4 ϩ T cell help (20).…”

“…ϩ T cell responses can be generated in the absence of CD4 ϩ T cell help, most studies have suggested that CD4 ϩ T cells are absolutely required to either generate (5,6,15) or support the survival of CD8 ϩ memory T cells (7,16,17). This connection may involve CD40 ligation on activated CD8…”

A call to cellular & humoral arms: Enlisting cognate T cell help to develop broad-spectrum vaccines against influenza A

“…[2][3][4] To be effective, an influenza vaccine must be designed and manufactured prior to the beginning of an influenza season or pandemic, and must induce immune responses that recognize the circulating strain. 5 Through global surveillance, the human influenza strains that pose the greatest risk for infectious spread can be chosen and influenza vaccines can be formulated accordingly.…”

“…93 This may be in part a function of natural infection since native viral proteins NS1 and PB2 are known to inhibit the immune response. 94 It is important to note that the CD4+ T helper cells enhance and amplify cytotoxic T cell (CTL) immune responses and have been shown to be important to fitness of CD8+ T-cell memory in influenza 4 and to the longevity of CD8+ T cell responses in other viral models. 95 How memory is maintained after acute infections is not yet known.…”

“…In the mouse model, lifelong CD4 responses to influenza have been shown to be maintained. 4,38,103,109 In humans, the study of CD4 durability is complicated by undocumented infections, but preliminary studies suggest that CD4 responses last at least several years post infection. 96 The effect of CD4+ T cells and their contribution to priming the immune response is most evident when examining the effect of previous influenza exposure on the titer of antibody following re-vaccination.…”