Cutting Edge: Batf3 Expression by CD8 T Cells Critically Regulates the Development of Memory Populations

Protective immunity against pathogens depends on the efficient generation of functionally diverse effector and memory T lymphocytes. However, whether plasticity during effector-to-memory CD8 + T cell differentiation affects memory lineage specification and functional versatility remains unclear. Using genetic fate mapping analysis of highly cytotoxic KLRG1 + effector CD8 + T cells, we demonstrated that KLRG1 + cells receiving intermediate amounts of activating and inflammatory signals, downregulated KLRG1 during the contraction phase in a Bach2 -dependent manner, and differentiated into all memory T cell linages, including CX 3 CR1 int peripheral memory cells and tissue-resident memory cells. ‘ExKLRG1’ memory cells retained high cytotoxic and proliferative capacity distinct from other populations, which contributed to effective anti-influenza and anti-tumor immunity. Our work demonstrates that developmental plasticity of KLRG1 + effector CD8 + T cells is important in promoting functionally versatile memory cells and long-term protective immunity. Herndler-Brandstetter et al. demonstrate that KLRG1 + IL-7Rα + effector CD8 + T cells downregulate KLRG1 in a Bach2 -depenent manner and differentiate into long-lived circulating and tissue-resident ‘exKLRG1’ memory cells. Developmental plasticity of KLRG1 + effector cells therefore drives functional diversity within memory T cell lineages and promotes enhanced anti-influenza and anti-tumor immunity. Show more

Despite the crucial role of tissue-resident memory T (Trm) cells in protective immunity, their priming remains poorly understood. Here, we have shown differential priming requirements for Trm versus circulating memory CD8(+) T cells. In vaccinia cutaneous-infected mice, DNGR-1-mediated crosspresentation was required for optimal Trm cell priming but not for their skin differentiation or for circulating memory T cell generation. DNGR-1(+) dendritic cells (DCs) promoted T-bet transcription-factor induction and retention of CD8(+) T cells in the lymph nodes (LNs). Inhibition of LN egress enhanced Trm cell generation, whereas genetic or antibody blockade of DNGR-1 or specific signals provided during priming by DNGR-1(+) DCs, such as interleukin-12 (IL-12), IL-15, or CD24, impaired Trm cell priming. DNGR-1 also regulated Trm cell generation during influenza infection. Moreover, protective immunity depended on optimal Trm cell induction by DNGR-1(+) DCs. Our results reveal specific priming requirements for CD8(+) Trm cells during viral infection and vaccination. Show more

Classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) feature high expression of activator protein-1 (AP-1) transcription factors, which regulate various physiological processes but also promote lymphomagenesis. The AP-1 factor basic leucine zipper transcription factor, ATF-like 3 (BATF3), is highly transcribed in cHL and ALCL; however, its functional importance in lymphomagenesis is unknown. Here we show that proto-typical CD30+ lymphomas, namely cHL (21/30) and primary mediastinal B-cell lymphoma (8/9), but also CD30+ diffuse large B-cell lymphoma (15/20) frequently express BATF3 protein. Mass spectrometry and co-immunoprecipitation established interactions of BATF3 with JUN and JUNB in cHL and ALCL lines. BATF3 knockdown using short hairpin RNAs was toxic for cHL and ALCL lines, reducing their proliferation and survival. We identified MYC as a critical BATF3 target and confirmed binding of BATF3 to the MYC promoter. JAK/STAT signaling regulated BATF3 expression, as chemical JAK2 inhibition reduced and interleukin 13 stimulation induced BATF3 expression in cHL lines. Chromatin immunoprecipitation substantiated a direct regulation of BATF3 by STAT proteins in cHL and ALCL lines. In conclusion, we identified STAT-mediated BATF3 expression that is essential for lymphoma cell survival and promoted MYC activity in cHL and ALCL, hence we recognized a new oncogenic axis in these lymphomas. Show more