| The adaptive immune response has evolved multiple mechanisms for protection against invading pathogens. CD8 T cells mediate protection against intracellular pathogens such as viruses by recognizing and killing infected cells. Meanwhile, the B cell response provides antibody at sites of pathogen entry to opsonize or neutralize invading pathogens. Additionally, CD4 T cell responses are important for activating CD8 T cell and B cell responses. Although the role of CD4 T cells in initiating B cell responses is well established, less is understood about how CD4 T cells initiate or sustain CD8 T cell responses. This question has become increasingly important as we try to understand why CD8 T cell responses fail during chronic viral infections such as HIV, HBV and HCV. In these chronic infections there is often a lack of a CD4 T cell response, and this parallels functional exhaustion of the CD8 T cells. To better understand the interplay between CD4 T cell responses and CD8 T cell exhaustion we examined the effects of altering CD4 T cell and B cell responses during chronic LCMV infection of mice. We first examined the question of how transient removal of CD4 T cell help affects long-term CD8 T cell responses. Secondly, we determined whether improving CD4 T cell help would affect CD8 T cell exhaustion. A transient one-week blockade of CD4 T cell help via administration of alphaCD40L blocking antibody beginning at two weeks post infection had no direct effect on the function of CD8 T cells but resulted in reduced CD4 T cell function and decreased levels of humoral immunity. This decreased CD4 T cell response then resulted in greater CD8 T cell exhaustion and impaired viral clearance. On the other hand, adoptive transfer of virus specific CD4 T cells during chronic LCMV infection restored function in exhausted CD8 T cells and also enhanced antibody responses. This rescue was observed for several CD8 T cell epitopes, was synergized by alphaPD-L1 treatment, and resulted in improved viral control in treated animals. Thus, these studies provide insights into how CD4 T cells and B cells can affect CD8 T cell programming and how one might design therapies to combat chronic infections in humans. |
