Abstract
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.
Highlights
CD8+ T cells are critical to protection against infection by intracellular pathogens, including liver stage malaria parasites
CD4+ helper T cells are necessary for CD8+ T cell responses to c-spz We have previously shown that CD4+ cells are critical for optimal priming of both endogenous polyclonal CD8+ T cells and antigen-specific TCR-Tg CD8+ T cells following immunization with irradiated P. yoelii sporozoites [5]
Memory CD8+ T cells induced by irradiated malaria sporozoites are critical for elimination of liver stage parasites and the optimal development of primary effector CD8+ T cells to sporozoite antigen is dependent on the presence of CD4+ helper T cells [5]
Summary
CD8+ T cells are critical to protection against infection by intracellular pathogens, including liver stage malaria parasites. T cell priming by c-spz occurs primarily in the skin-draining lymph node after parasite inoculation in the skin by either needle or the bite of an infected mosquito, followed by dissemination of effector T cells throughout the body, including the spleen and liver [4] This priming in the lymph node is closely dependent on CD4+ cells and the absence thereof results in a reduced effector population [5]. This dependence on helper T cells at such an early time point is unique among models of CD8+ T cell priming, which often demonstrate unaltered primary CD8+ T cell responses to pathogens in the absence of helper T cells [6,7,8,9,10], with defects only apparent in functional recall of resting memory cells [7,9,11]. In view of the clear and early dependence of c-spzinduced CD8+ T cells on CD4+ T cells, we sought to characterize the effect of helper T cells on the functional development of antiparasite CD8+ T cells
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