Potent induction of long-term CD8+ T cell memory by short-term IL-4 exposure during T cell receptor stimulation

Abstract

An important goal of vaccination is to achieve long-term survival of functional memory T cells. Using a MHC-compatible adoptive transfer system, we show here that a short, 3-day IL-4 but not IL-2 or IL-12 exposure during in vitro T cell receptor stimulation of naive CD8 ؉ T cells induced long-lasting in vivo memory. Such long-term memory CD8 ؉ T cells expressed antigen-specific cytotoxicity and the potential for IFN-␥ and IL-4 production. Our results support the concept that functional T cell longevity can be regulated by cytokines during initial antigen encounter and provide a rational foundation for vaccine development. They also may have implications in formulating optimal therapeutic regimens of ex vivo expanded autologous cancer-and HIV-specific CD8 ؉ T cells. In addition, the availability of large numbers of memory CD8 ؉ T cells generated through our high-efficiency system should facilitate progress in the molecular dissection of CD8 ؉ T cell memory development.

Evaluation of the immunogenicity and protective efficacy of Killed Leishmania donovani antigen along with different adjuvants against experimental visceral leishmaniasis

“…The evidences that early IL-4 is needed to drive Th1 differentiation [52] and to enhance IFN-γ secretion [53,54] imply that early IL-4 production does not hinder the Th1 response. It is in line with observations revealing that IL-4 is crucial for the priming of long-term CD8 + T-cell memory responses [55][56][57].…”

Donor lymphocyte infusion leads to diversity of specific T cell responses and reduces regulatory T cell frequency in clinical responders

“…It has been shown in vitro that in the presence of IL-4, naïve CD8 + T cells were able to develop into long-term memory CD8 + cells. 48 Morris et al 49 showed in vitro, that endogenously produced IL-4 is a direct stimulator of proliferation of antigen-and pathogen-induced CD8 + T cells and it can activate both naïve and memory/activated CD8 + T cells. In our analysis, we can only speculate that a higher IL-4 level might contribute to the expansion of LAA-specific T cells and the response to DLI.…”

IL-4 acts as a potent stimulator of IFN-γ expression in CD8+ T cells through STAT6-dependent and independent induction of Eomesodermin and T-bet

“…In addition, IL-4 is required for the development of a recently described population of innate CD8+ T cells in mice with a memory-like phenotype and constitutive expression of Eomes [28]. IL-4 has also been shown been shown to promote memory development in adaptive CD8+ T cells in vivo , as well as their survival and proliferation [14, 29, 30]. With regards to memory development, in the current studies we also found that blockade of IL-4 in CD3/28-mAb stimulated pan-T cell cultures or addition of IL-4 to CD3/CD28 mAb-stimulated purified CD8+ T cells inhibited or promoted the generation of CD44 hi memory phenotype CD8+ T cells respectively (data not shown).…”

“…However, in each of these studies, it is unclear if IL-4 acts directly upon CD8+ T cells to regulate IFN-γ synthesis or cytotoxic activity or indirectly through action upon another cell type. Moreover, IL-4 has been shown to be required for the generation of memory CD8+ T cells which compared to naïve T cells synthesize much greater quantities of IFN-γ and cytotoxic effector molecules [14]. Therefore, an apparent role for IL-4 in the induction of IFN-γ and cytoxicity as revealed upon ex vivo stimulation could reflect a role for this cytokine in induction of memory cell formation in vivo rather than its ability to directly regulate these responses per se .…”