CD4⁺ T cells modulate expansion and survival but not functional properties of effector and memory CD8⁺ T cells induced by malaria sporozoites

CD4⁺ helper T cells are critical orchestrators of immune responses to infection and vaccination. During primary responses, naïve CD8⁺ T cells may need "CD4 help" for optimal development of memory populations. The immunological factors attributed to CD4 help depend on the context of immunization and vary depending on the priming system. In response to immunization with radiation-attenuated Plasmodium yoelii sporozoites, CD8⁺ T cells in BALB/c mice fail to generate large numbers of effector cells without help from CD4⁺ T cells - a defect not observed in most systems. Given this unique early dependence on CD4 help, we evaluated the effects of CD4⁺ cells on the development of functional properties of CD8⁺ T cells and on their ability to abolish infection. First, we determined that this effect was not mediated by CD4⁺ non-T cells and did not involve CD1d-restricted NKT cells. We found that CD8⁺ T cells induced by sporozoites without CD4 help formed memory populations severely reduced in magnitude that could not limit parasite development in the liver. The inability of these "helpless" memory T cells to protect is not a result of defects in effector function, as their capacity to produce cytokines and undergo cytotoxic degranulation was indistinguishable from control memory T cells. These data indicate that CD4⁺ T help may not be necessary to develop the functional attributes of CD8⁺ T cells; however they are crucial to ensure the survival of effector and memory cells induced in primary responses.