Nicholas J. Maurice

Numerous transcriptional regulators have been associated with the differentiation pathways that lead to recirculating vs. tissue-resident memory T cells. However, it is unclear whether independent, coordinated expression of these regulators is required to determine residency vs. recirculation or whether there is a hierarchy, with some factors playing a dominant role in controlling T cell trafficking. We report that ablation of the gene encoding Kruppel-like factor 2 (KLF2) during CD8 ⁺ T cell activation leads to rapid transcriptional reprogramming, such that effector T cells fail to recirculate and prematurely acquire canonical phenotypic and transcriptional characteristics of resident memory cells (T _RM ). Klf2 -deficient memory CD8 ⁺ T cells retained the capacity to undergo recall responses, including in vivo pathogen control. These data suggest that KLF2 diverts CD8 ⁺ T cells from the T _RM differentiation program. In contrast, ablation of another member of the KLF family, KLF3, enhanced differentiation of some recirculating T cell subsets and limited production of T _RM in lymphoid tissues. However, both KLF2 and KLF3 were required for differentiation of long-lived effector cells, suggesting cooperation between these factors in some situations. These findings indicate that KLFs occupy a central nexus in coordinating activated CD8 ⁺ T cell differentiation and trafficking.

Memory CD8⁺ T (T_mem) cells are activated into innate-like killers by cytokines, including interleukin-12 (IL-12), IL-15 and IL-18; but mechanisms regulating this phenomenon (termed bystander activation) are unclear. Here we show that basal IL-4 signals antagonize IL-18 sensing and subsequent interferon-γ production during T_mem cell bystander activation. IL-4 treatment can act directly on T_mem cells in a STAT6-dependent manner to limit interferon-γ-mediated control of a bystander bacterial infection. IL-4 does not simply block bystander activation but tunes effector molecule expression. Strain-specific defects in bystander activation of homeostatic T_mem cells partially relates to IL-4 exposure, but these differences are erased in T_mem cells produced by T cell antigen receptor activation, leading to uniform IL-18 receptor expression and capacity for bystander activation/cytotoxicity. Our data demonstrate that bystander activation by inflammatory cytokines is subject to regulation by both IL-4 and prior antigen experience. These findings underscore the importance of the cytokine milieu in dictating bystander-mediated pathogen control.

Antigen specificity and functionality of predominant TCRs from tumors from immunotherapy treated mice.

Single cell transcriptional atlas following anti-PDL1 or agonistic anti-CD40

CD4 T cells and tumor antigen are required for anti-CD40 driven TSTEM accumulation in PDA

Comparison of human and murine tumor-infiltrating CD8 T cells.

IL15C synergizes with immunotherapy to target poorly immunogenic KPC2 tumors

CD8 T cell differentiation in PDA.

IL-15C promotes the activity of dual therapy by promoting T-bet in tumor-infiltrating T cells