The Central Memory CD4+ T Cell Population Generated duringLeishmania majorInfection Requires IL-12 to Produce IFN-γ

Abstract

Central memory CD4+ T cells provide a pool of lymph node-homing, Ag-experienced cells that are capable of responding rapidly after a secondary infection. We have previously described a population of central memory CD4+ T cells in Leishmania major-infected mice that were capable of mediating immunity to a secondary infection. In this study, we show that the Leishmania-specific central memory CD4+ T cells require IL-12 to produce IFN-γ, demonstrating that this population needs additional signals to develop into Th1 cells. In contrast, effector cells isolated from immune mice produced IFN-γ in vitro or in vivo in the absence of IL-12. In addition, we found that when central memory CD4+ T cells were adoptively transferred into IL-12-deficient hosts, many of the cells became IL-4 producers. These studies indicate that the central memory CD4+ T cell population generated during L. major infection is capable of developing into either Th1 or Th2 effectors. Thus, continued IL-12 production may be required to ensure the development of Th1 cells from this central memory T cell pool, a finding that has direct relevance to the design of vaccines dependent upon central memory CD4+ T cells.

Dynamicity of Immune Regulation during Visceral Leishmaniasis

“…Central memory CD4 + T cell population generated during L. major infection is capable of developing into either Th1 or Th2 effectors. Under the influence of IL-12, Leishmania specific central memory CD4 + T cells get differentiated into IFN-producing Th1 cells (Pakpour et al, 2008). Low dose L. major promotes a transient Th2 response that is downregulated by IFN-producing CD8 + T cells which may contribute to rapid resolution of secondary lesions (Uzonna et al, 2004;Wang et al, 1993).…”

Cutaneous Leishmaniasis: Update on Vaccine Development

“…IL 12 promotes a T H 1 response in a mouse of model of CL for long-term immunity. 85,86 Consistent with this concept, inclusion of IL-12 as part of a DNA vaccine cocktail improved protection against L major challenge. [87][88][89] However, administration of IL-12 in humans is toxic; thus, this strategy is not suitable for human vaccination.…”

“…Adjuvants improve the efficacy of Leishmania vaccine candidates by triggering high levels of IL-12 and IFN-γ expression, both of which play vital roles in long-term immunological memory. 85,86,96 The TLR7 agonist Aldara and TLR9 agonist CpG DNA exhibited therapeutic antileishmanial properties (reviewed in the study by Raman et al 97 ). In contrast, TLR2 agonist Pam3CSK4 led to conflicting results depending on the mouse model used.…”

Regulation of immunity at tissue sites of inflammation

“…IL-10 auto-regulates Th1 cell production of IFNc directly or indirectly through modulation of macrophage function effector cytokine production from both Th1 and Th2 effector cells by enhancing T-cell expression of the costimulatory molecule ICOS [33]. More recently, IL-12 has been implicated in driving IFNc production from central memory T cells [34], a subset of memory cells that can confer long-term immunity to L. major in the absence of persistent parasites [35]. For Th2 cells, continued expression of GATA3 expression appears critical for high-level cytokine production by Th2 effectors [36].…”