Which antigen-presenting cells are involved in Tfh responses in humans remains unclear. Durand et al. show that human tonsil cDC2 and CD14+ macrophages provide Tfh polarizing signals to CD4+ T cells in distinct locations within tonsil, playing sequential roles in Tfh induction.

The AMP-activated kinase (AMPK) is a major energy sensor metabolic enzyme that is activated early during T cell immune responses but its role in the generation of effector T cells is still controversial. Using both in vitro and in vivo models of T cell proliferation, we show herein that AMPK is dispensable for early TCR signaling and short-term proliferation but required for sustained long-term T cell proliferation and effector/memory T cell survival. In particular, AMPK promoted accumulation of effector/memory T cells in competitive homeostatic proliferation settings. Transplantation of AMPK-deficient hematopoïetic cells into allogeneic host recipients led to a reduced graft-versus-host disease, further bolstering a role for AMPK in the expansion and pathogenicity of effector T cells. Mechanistically, AMPK expression enhances the mitochondrial membrane potential of T cells, limits reactive oxygen species (ROS) production, and resolves ROS-mediated toxicity. Moreover, dampening ROS production alleviates the proliferative defect of AMPK-deficient T cells, therefore indicating a role for an AMPK-mediated ROS control of T cell fitness.

Under lymphopenia, fast proliferation of peripheral lymphocytes, driven by the availability of interleukin-7 and the engagement of the T cell receptor, results in a large pool of effector/memory T cells that may potentiate anti-tumor immunotherapies but also lead to auto-immune complications.Naïve, effector and memory CD4 T lymphocytes display particular energy metabolism and it has been shown that fine-tuning of cell metabolism might govern T cell differentiation.However, whether T cell metabolism controls homeostatic proliferation is unknown. Here, we report that deficiency in the energy sensor metabolic enzyme AMP-activated kinase (AMPK) results in reduced accumulation of effector/memory T cells during the course of homeostatic proliferation. Accordingly, hematopoietic stem cell transplantation of AMPK-deficient T cells into allogeneic recipient led to a reduced graft-versus-host disease. Moreover, we show that AMPK expression enhances the mitochondrial potential of T cells, limits reactive oxygen species (ROS) production, and resolves ROS-mediated toxicity. Dampening ROS production alleviates the proliferative defect of AMPK-deficient T cells, therefore indicating a role for an AMPK-mediated ROS control of homeostatic proliferation.

Distinct lymphocyte subpopulations display discrete metabolic profiles and are differently affected by metabolic resource variations, making the analysis of lymphocyte survival in a complex tissue in response to metabolic stress highly challenging. Here we describe a flow cytometry-based method allowing simultaneous cell identification and viable cell counting in mixed lymphocyte populations without extensive cell subset purification procedures. The example provided herein illustrates the role of AMPK in T lymphocyte survival in response to the mitochondrial poison oligomycin.