Abstract
<jats:p>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 (TGFβ) 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 TGFβ 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 TGFβ 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 TGFβ 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 TGFβ 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 TGFβ signalling and immune regulation is not linear. TGFβ 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.</jats:p>