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Innate lymphoid cells (ILCs) participate in tissue homeostasis, inflammation, and early immunity against infection. It is unclear how ILCs acquire effector function and whether these mechanisms differ between organs. Through multiplexed single-cell mRNA sequencing, we identified cKit + CD127 hi TCF-1 hi early differentiation stages of T-bet + ILC1s. These cells were present across different organs and had the potential to mature toward CD127 int TCF-1 int and CD127 - TCF-1 - ILC1s. Paralleling a gradual loss of TCF-1, differentiating ILC1s forfeited their expansion potential while increasing expression of effector molecules, reminiscent of T cell differentiation in secondary lymphoid organs. The transcription factor Hobit was induced in TCF-1 hi ILC1s and was required for their effector differentiation. These findings reveal sequential mechanisms of ILC1 lineage commitment and effector differentiation that are conserved across tissues. Our analyses suggest that ILC1s emerge as TCF-1 hi cells in the periphery and acquire a spectrum of organ-specific effector phenotypes through a uniform Hobit-dependent differentiation pathway driven by local cues., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Antiviral CD8 + T cell responses are characterized by an initial activation/priming of T lymphocytes followed by a massive proliferation, subset differentiation, population contraction and the development of a stable memory pool. The transcription factor BATF3 has been shown to play a central role in the development of conventional dendritic cells, which in turn are critical for optimal priming of CD8 + T cells. Here we show that BATF3 was expressed transiently within the first days after T cell priming and had long-lasting T cell-intrinsic effects. T cells that lacked Batf3 showed normal expansion and differentiation, yet succumbed to an aggravated contraction and had a diminished memory response. Vice versa, BATF3 overexpression in CD8 + T cells promoted their survival and transition to memory. Mechanistically, BATF3 regulated T cell apoptosis and longevity via the proapoptotic factor BIM. By programing CD8 + T cell survival and memory, BATF3 is a promising molecule to optimize adoptive T cell therapy in patients.

Regulatory T cells (T reg cells), which have abundant expression of the interleukin 2 receptor (IL-2R), are reliant on IL-2 produced by activated T cells. This feature indicates a key role for a simple network based on the consumption of IL-2 by T reg cells in their suppressor function. However, congenital deficiency in IL-2R results in reduced expression of the T reg cell lineage-specification factor Foxp3, which has confounded experimental efforts to understand the role of IL-2R expression and signaling in the suppressor function of T reg cells. Using genetic gain- and loss-of-function approaches, we found that capture of IL-2 was dispensable for the control of CD4 + T cells but was important for limiting the activation of CD8 + T cells, and that IL-2R-dependent activation of the transcription factor STAT5 had an essential role in the suppressor function of T reg cells separable from signaling via the T cell antigen receptor.

Lymphocytes are essential in innate and adaptive immunity. Recent insights suggest that some innate lymphocytes execute functions with adaptive characteristics, while adaptive lymphocytes can operate in ways reminiscent of innate cells. Rather than partitioning lymphocytes according to the type of effector function they execute, we propose that a relevant discrimination relates to the existence of conventional T cells in a naive state. The naive state can be seen as an actively repressed condition that supports T cell diversity and enables the flexible differentiation of effector cells in a manner that best addresses the antigenic challenge. We discuss these considerations in the context of the relative roles of innate lymphoid cells and antigen-experienced T cells in the immune system.