The Development of Functional CD8 T Cell Memory afterListeria monocytogenesInfection Is Not Dependent on CD40

Abstract

The immunologic requirements for generating long-lived protective CD8 T cell memory remain unclear. Memory CD8 populations generated in the absence of CD4 Th cells reportedly have functional defects, and at least a subset of CD8 T cells transiently express CD40 after activation, suggesting that direct CD4-CD8 T cell interactions through CD40 may influence the magnitude and functional quality of memory CD8 populations. To ascertain the role of CD40 in such direct T cell interactions, we investigated CD8 T cell responses in CD40−/− mice after infection with Listeria monocytogenes, an intracellular bacterium that induces APC activation and thus priming of CD8 T cells independently of CD4 Th cell help through CD40. In this study we show that memory CD8 T cells generated in CD40-deficient mice show in vivo cytotoxicity and cytokine production equivalent to CD8 memory T cells from wild-type mice. Upon secondary Listeria infection, CD40−/− memory CD8 T cells expand to greater numbers than seen in wild-type mice. These results indicate that CD40 ligation on CD8 T cells, although reportedly a part of CD8 T cell memory development in an H-Y-directed response, is not needed for the development of functional memory CD8 T cell populations after Listeria infection.

Kinetic and Mechanistic Requirements for Helping CD8 T Cells

“…However, the presence of CD40 was entirely dispensable in our prime-boost system, as primary and secondary CD8 T cell responses were comparable in wild-type and in CD40-deficient mice (25). This is in line with previous studies, showing that in many pathogen infections CD40 and CD40L are dispensable for induction of CD8 T cell responses (24,25,29). Furthermore, CD8 T cells can transiently express CD40 upon activation and might therefore directly interact with CD40L-expressing Th cells (27).…”

“…One report indicated that CD40L on the surface of CD4 Th cells can directly interact with CD40 expressed by CD8 T cells (27) and it was proposed that this direct interaction between CD4 and CD8 T cells was a prerequisite for the helpreceiving mechanism of CD8 T cells. However, these findings could not be confirmed in other experimental systems (24,25,29). In a recent study using intravital microscopy, it was suggested that CD4 T cells directly, or indirectly via activation of dendritic cells (DCs), produce the chemokines CCL3 and CCL4.…”

CD4 + T cell regulation of CD25 expression controls development of short-lived effector CD8 + T cells in primary and secondary responses

“…Although CD40-mediated activation of DC may be one mechanism to promote CD8 + T cell responses, IL-2 production may also augment the CD8 + T cell response either alone or in concert with CD40 signaling. For instance, no defect has been observed for memory CD8 + T cells developing in the absence of CD40 signaling during LM infection (33). In contrast, CD40 signaling appears to be critical for full differentiation of memory CD8 + T cells following influenza A virus, murine γ-herpesvirus, and intranasal vaccinia virus infections (23,29).…”

CD4 Help Regulates Expression of Crucial Genes Involved in CD8 T Cell Memory and Sensitivity to Regulatory Elements

“…Similar conclusions are more controversial in infectious models. Two reports studying Listeria Monocytogenes responses show no role for CD40/CD40L interactions in either the primary or the secondary response (50,51), whereas many others infectious studies describe a deficient secondary response in the absence of CD40/CD40L interactions (13,(52)(53)(54)(55). A study by Lee et al (56) suggests a role for CD40 on APCs but not on CD8 T cells during secondary response in a model of influenza immunization.…”