Abstract
<jats:title>Abstract</jats:title> <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 <jats:italic>Leishmania donovani</jats:italic> 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> <jats:sec> <jats:title>Author summary</jats:title> <jats:p> Visceral leishmaniasis (VL) is a potentially fatal disease caused by <jats:italic>Leishmania</jats:italic> parasites. The immune system must generate a strong enough response to control these parasites while preventing excessive inflammation that can damage tissues. We investigated how transforming growth factor-beta (TGFβ), an important regulator of immune responses, helps maintain this balance. Using mice in which signalling by TGFβ was either increased or removed specifically in T cells, we found that this pathway strongly influenced the development and function of CD4⁺ T cells during infection. Increasing signalling suppressed the expansion of these cells and their development into inflammatory cells associated with parasite control. In contrast, removing signalling enhanced these responses and improved early parasite control, but also reduced the development of regulatory T cells that can limit inflammation. By studying parasite-specific T cells directly, we showed that many of these effects resulted from TGFβ acting within the T cells themselves. Our findings show that TGFβ does more than simply suppress immunity during VL. It helps determine the balance between CD4⁺ T cell responses that control parasites and those that regulate inflammation, providing new insight into how immunity is shaped during chronic infection. </jats:p> </jats:sec>