IL-7 receptor expression provides the potential for long-term survival of both CD62Lhigh central memory T cells and Th1 effector cells during Leishmania major infection.

Infection with the intracellular protozoan parasite Leishmania major induces a state of concomitant immunity wherein secondary immunity is dependent upon the persistence of the original pathogen. Our laboratory has described two populations of Leishmania-induced CD4(+) T cells that contribute to immunity: CD62L(high) central memory T (T(CM)) cells and CD62L(low) effector T cells. To determine whether the prosurvival cytokine IL-7 contributes to maintaining these T cells, we examined expression of the IL7R on CD4(+) T cells activated during L. major infection. We found that T(CM) cells present in chronically infected mice expressed high levels of the IL7R. However, in addition to the expression of the IL7R by T(CM) cells, CD62L(low) cells responding to L. major infection expressed the IL7R. Additional experiments revealed that a large percentage of the IL7R(high)CD62L(low) cells were Th1 cells, based on transcription at the IFN-gamma locus and up-regulation of the Th1-promoting transcription factor T-bet. The up-regulation of T-bet did not prevent IL7R expression by L. major-responding CD4(+) T cells, nor did the absence of T-bet result in increased IL7R expression. Finally, blockade of IL7R signaling decreased the number of T-bet(+)CD4(+) T cells, reduced IFN-gamma production, and inhibited delayed-type hypersensitivity responses in immune mice challenged with L. major, indicating that IL7R signaling contributes to the maintenance of Th1 effector cells. Thus, both T(CM) and Th1 effector cells can express the IL7R during chronic L. major infection, which provides a potential means for their long-term survival in addition to the presence of persisting parasites.

PTEN inhibits IL-2 receptor-mediated expansion of CD4+ CD25+ Tregs.

One of the greatest barriers against harnessing the potential of CD4+ CD25+ Tregs as a cellular immunotherapy is their hypoproliferative phenotype. We have previously shown that the hypoproliferative response of Tregs to IL-2 is associated with defective downstream PI3K signaling. Here, we demonstrate that targeted deletion of the lipid phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome 10) regulates the peripheral homeostasis of Tregs in vivo and allows their expansion ex vivo in response to IL-2 alone. PTEN deficiency does not adversely affect either the thymic development or the function of Tregs, which retain their ability to suppress responder T cells in vitro and prevent colitis in vivo. Conversely, reexpression of PTEN in PTEN-deficient Tregs as well as in activated CD4+ T cells inhibits IL-2-dependent proliferation, confirming PTEN as a negative regulator of IL-2 receptor signaling. These data demonstrate that PTEN regulates the "anergic" response of Tregs to IL-2 in vitro and Treg homeostasis in vivo and indicate that inhibition of PTEN activity may facilitate the expansion of these cells for potential use in cellular immunotherapy.

Cutting edge: Th2 response induction by dendritic cells: a role for CD40.

We investigated the influence of dendritic cell (DC) CD40 expression on Th2 and Th1 development by in vivo transfer of Ag-pulsed bone marrow-derived DC generated from wild-type (WT) or CD40(-/-) mice. Contrary to expectation, CD40(-/-) DC primed with Ag that inherently induce a Th2 response (soluble egg Ag from Schistosoma mansoni) failed to induce a Th2 response or any compensatory Th1 response, whereas CD40(-/-)DC primed with Ag that inherently induce a Th1 response (Propionibacterium acnes) generated a competent Th1 response. Thus, DC expression of CD40 is a prerequisite for initiation of Th2, but not Th1, responses by these Ag. Consistent with this, CD154(-/-) mice, unlike WT mice, failed to mount a Th2 response when directly injected with schistosome eggs but mounted a normal Th1 response after challenge with P. acnes. CD40-CD154 interaction can therefore play a major role in Th2 response induction.

Notch signaling augments T cell responsiveness by enhancing CD25 expression.

Notch receptors signal through a highly conserved pathway to influence cell fate decisions. Notch1 is required for T lineage commitment; however, a role for Notch signaling has not been clearly defined for the peripheral T cell response. Notch gene expression is induced, and Notch1 is activated in primary CD4(+) T cells following specific peptide-Ag stimulation. Notch activity contributes to the peripheral T cell response, as inhibition of endogenous Notch activation decreases the proliferation of activated T cells in a manner associated with the diminished production of IL-2 and the expression of the high affinity IL-2R (CD25). Conversely, forced expression of a constitutively active Notch1 in primary T cells results in increased surface expression of CD25, and renders these cells more sensitive to both cognate Ag and IL-2, as measured by cell division. These data suggest an important role for Notch signaling during CD4(+) T cell responses, which operates through augmenting a positive feedback loop involving IL-2 and its high affinity receptor.