TGF-β signalling regulates the balance between protective and regulatory CD4+ T cell responses in visceral leishmaniasis

Visceral leishmaniasis (VL) is a potentially fatal parasitic disease in which effective immunity requires sufficient inflammation to control parasites while limiting immune-mediated tissue damage. Transforming growth factor-beta (TGF{beta}) is an important regulator of immune homeostasis and has been implicated in VL, but how it directly controls parasite-specific CD4+ T cell responses remains poorly understood. We used complementary transgenic mouse models with either enhanced or ablated TGF{beta} signalling in T cells during Leishmania donovani infection, combined with adoptive co-transfer of parasite-specific CD4+ T cells to distinguish cell-intrinsic effects. Enhanced TGF{beta} signalling impaired hepatic parasite control and suppressed CD4+ T cell immunity, reducing T helper 1 (Th1) cell differentiation, proliferation, accumulation of antigen-experienced cells, and expression of cytolytic molecules. Conversely, ablation of TGF{beta} signalling improved parasite control and promoted CD4+ T cell expansion and Th1 cell differentiation, while increasing expression of cytolytic molecules and reducing interleukin-10-producing type 1 regulatory T (Tr1) cells. Adoptive co-transfer experiments confirmed that TGF{beta} directly restrained the expansion and Th1 cell differentiation of parasite-specific CD4+ T cells and their acquisition of cytolytic features. Loss of signalling also impaired development of Tr1 cells and reduced expression of several chemokine receptors and co-inhibitory molecules associated with their regulatory function. However, enhanced signalling did not increase Tr1 cell development, indicating that the relationship between TGF{beta} signalling and immune regulation is not linear. TGF{beta} is a key cell-intrinsic regulator of CD4+ T cell fate during experimental VL. Rather than acting solely as a general suppressor of inflammation, it calibrates the balance between protective and regulatory immunity by controlling CD4+ T cell expansion, differentiation and effector function.