IL-2 Is Required for the Activation of Memory CD8+ T Cells via Antigen Cross-Presentation

Abstract

Dendritic cells (DCs) are capable of capturing exogenous Ag for the generation of MHC class I/peptide complexes. For efficient activation of memory CD8+ T cells to occur via a cross-presentation pathway, DCs must receive helper signals from CD4+ T cells. Using an in vitro system that reflects physiologic recall memory responses, we have evaluated signals that influence helper-dependent cross-priming, while focusing on the source and cellular target of such effector molecules. Concerning the interaction between CD4+ T cells and DCs, we tested the hypothesis that CD40 engagement on DCs is critical for IL-12p70 (IL-12) production and subsequent stimulation of IFN-γ release by CD8+ T cells. Although CD40 engagement on DCs, or addition of exogenous IL-12 are both sufficient to overcome the lack of help, neither is essential. We next evaluated cytokines and chemokines produced during CD4+ T cell/DC cross talk and observed high levels of IL-2 produced within the first 18–24 h of Ag-specific T cell engagement. Functional studies using blocking Abs to CD25 completely abrogated IFN-γ production by the CD8+ T cells. Although required, addition of exogenous IL-2 did not itself confer signals sufficient to overcome the lack of CD4+ T cell help. Thus, these data support a combined role for Ag-specific, cognate interactions at the CD4+ T cell/DC as well as the DC/CD8+ T cell interface, with the helper effect mediated by soluble noncognate signals.

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

“…Either way, in the absence of CD4 + T cells, CD25 was poorly up-regulated on responding CD8 + T cells after VV, VSV, and LM infections. This is in line with previous studies that have demonstrated that CD4 + T cell help regulates CD25 expression on CD8 + T cells after HSV-1 infection (35) and DC vaccination (36) and correlated with the CD4 + T cell dependence of these responses. In contrast, previous studies reported no CD4 + T cell or CD25 involvement in the primary CD8 + T cell response to LCMV and LM infections (18,19,27,28), although other studies support a role for CD4 + T cells in primary CD8 + T cell responses to these and other immunogens (21,22).…”

Interferon‐β therapy reduces CD4+ and CD8+ T‐cell reactivity in multiple sclerosis

“…40 The strong cell proliferation might have been in part the result of an unspecific expansion of pre-activated CD8 + T cells in our cultures; help provided by MOG-specific CD4 + T cells might then boost the reactivity of those CD8 + T cells even further. 41 Although a thorough analysis of whether the proliferative response we observed was indeed due to expansion of in vitro-stimulated, antigen-specific CD8 + T cells was beyond the scope of the present study, intriguing unconventional molecular mechanisms have been uncovered that may explain how CD8 + T cells respond to extracellular antigens. 42 APC such as dendritic cells are capable of cross-presentation by transferring exogenous proteins into the MHC class I pathway 43,44 or of directly transferring antigen-laden MHC class I complexes and costimulatory molecules to expanding CD4 + T cells, which then in turn are able to present these epitopes to CD8 + T cells and initiate a productive cytotoxic T-cell response.…”

Direct CD4 Help Provision following Interaction of Memory CD4 and CD8 T Cells with Distinct Antigen-Presenting Dendritic Cells

“…Help from CD4 T cells appears to be necessary at the time of initial antigenic activation of naive CD8 T cells (2,3), and CD4 T cells may also be required for longterm maintenance of memory CD8 T cells after Ag eradication (2)(3)(4). Deficient secondary CD8 T cell responses have also been reported when CD4 T cells are lacking at the time of Ag reactivation of memory CD8 T cells (5)(6)(7)(8)(9)(10), even if the CD8 T cells are generated in normal help conditions (5)(6)(7)(8)(9)(10). The nature of the help provided by CD4 T cells during priming of naive CD8 T cells and during maintenance or reactivation of memory cells is largely unknown and may differ in these three situations.…”