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Solid tumours are infiltrated by effector T cells with the potential to control or reject them, as well as by regulatory T (T reg ) cells that restrict the function of effector T cells and thereby promote tumour growth 1 . The anti-tumour activity of effector T cells can be therapeutically unleashed, and is now being exploited for the treatment of some forms of human cancer. However, weak tumour-associated inflammatory responses and the immune-suppressive function of T reg cells remain major hurdles to broader effectiveness of tumour immunotherapy 2 . Here we show that, after disruption of the CARMA1–BCL10–MALT1 (CBM) signalosome complex, most tumour-infiltrating T reg cells produce IFNγ, resulting in stunted tumour growth. Notably, genetic deletion of both or even just one allele of CARMA1 (also known as Card11 ) in only a fraction of T reg cells—which avoided systemic autoimmunity—was sufficient to produce this anti-tumour effect, showing that it is not the mere loss of suppressive function but the gain of effector activity by T reg cells that initiates tumour control. The production of IFNγ by T reg cells was accompanied by activation of macrophages and upregulation of class I molecules of the major histocompatibility complex on tumour cells. However, tumour cells also upregulated the expression of PD-L1, which indicates activation of adaptive immune resistance 3 . Consequently, blockade of PD-1 together with CARMA1 deletion caused rejection of tumours that otherwise do not respond to anti-PD-1 monotherapy. This effect was reproduced by pharmacological inhibition of the CBM protein MALT1. Our results demonstrate that partial disruption of the CBM complex and induction of IFNγ secretion in the preferentially self-reactive T reg cell pool does not cause systemic autoimmunity but is sufficient to prime the tumour environment for successful immune checkpoint therapy. Disruption of the CARMA1–BCL10–MALT1 (CBM) signalosome causes T reg cells to produce IFNγ and develop dominant anti-tumour activity in synergy with anti-PD-1 treatment, and in the absence of autoimmunity.

Tissue-resident memory T (T RM ) cells constitute a subpopulation of memory cells that reside in tissues instead of recirculating. CD8 + epithelial TRM (eT RM ) cells, which occupy the epithelium of sites like the skin, require transforming growth factor–β (TGF-β) for their development. Mani et al. found that α V integrin–expressing dendritic cells, which activate and present TGF-β, are key (see the Perspective by Farber). Surprisingly, this interplay did not occur in the skin or draining lymph nodes during T cell priming. Rather, resting naïve CD8 + T cells interacted with α V integrin–expressing migratory dendritic cells during immune homeostasis, reversibly preconditioning them to become eT RM cells upon activation. A potent cytokine is thus controlled in a context-dependent manner and preimmune T cell repertoires may be less uniform than previously presumed. Science , this issue p. eaav5728 ; see also p. 188 Resting naïve immunological T cells are poised to become tissue-resident memory cells after encounters with TGF-β–bearing dendritic cells. Epithelial resident memory T (eT RM ) cells serve as sentinels in barrier tissues to guard against previously encountered pathogens. How eT RM cells are generated has important implications for efforts to elicit their formation through vaccination or prevent it in autoimmune disease. Here, we show that during immune homeostasis, the cytokine transforming growth factor β (TGF-β) epigenetically conditions resting naïve CD8 + T cells and prepares them for the formation of eT RM cells in a mouse model of skin vaccination. Naïve T cell conditioning occurs in lymph nodes (LNs), but not in the spleen, through major histocompatibility complex class I–dependent interactions with peripheral tissue–derived migratory dendritic cells (DCs) and depends on DC expression of TGF-β–activating α V integrins. Thus, the preimmune T cell repertoire is actively conditioned for a specialized memory differentiation fate through signals restricted to LNs.

Epithelial resident memory CD8+ T cells (eTRM) have emerged as critical immune sentinels, playing a dominant role in protecting against barrier-invading pathogens and tumors, yet also mediating pathogenesis of autoimmune disorders. While their functional importance is established, determinants of eTRM differentiation have yet to be fully elucidated. One critical cytokine in eTRM differentiation is TGF-β, which is known to have a wide range of consequences on CD8+ T cell fate. A major regulator of this pleiotropism is the context by which TGF-β is activated from its latent form- thought to be tightly regulated by alphaV-integrins expressed on many cell types, including epithelial and dendritic cells (DC). Therefore, we sought to investigate the control of TGF-β activation during eTRM differentiation.We initially hypothesized that DC in the skin activate TGF-β for eTRM formation. Upon conditional deletion of TGF-β-activating alphaV-integrin in DC, we observed a profound deficiency in skin eTRM that was not due to effects in the skin during terminal differentiation or priming. Instead, we found that at homeostasis, DC-activated TGF-b on naïve CD8+ T cells epigenetically conditions them for eTRM formation in lymph nodes through non-cognate interactions of migratory DC with naïve CD8+ T cells. Collectively, our studies identify a novel stage of T cell differentiation, during which the pre-immune repertoire is actively conditioned for a specialized fate.Although terminal eTRM differentiation was independent of DC-activated TGF-β, other sources of TGF-β in the skin may regulate factors involved in long-term tissue retention. We therefore studied spatiotemporal dynamics to understand contributions of local TGF-β in the skin to eTRM differentiation. Through intravital microscopy of the skin, we found that TGF-β controls T cell migration into the epidermis via hair follicles by induction of chemokine receptor CCR6. This uncovers a new role for TGF-β in regulating spatial organization of cells within tissues. Finally, to extend our studies of spatiotemporal dynamics, we developed a GFP-Smad2 reporter system to further probe TGF-β signaling nuances in T cells in vivo.Together, these studies provide novel insights into the cellular dynamics mediating eTRM development and bolster our understanding of TGF-β signaling in the adaptive immune system.

Solid tumours are infiltrated by effector T cells with the potential to control or reject them, as well as by regulatory T (T ) cells that restrict the function of effector T cells and thereby promote tumour growth . The anti-tumour activity of effector T cells can be therapeutically unleashed, and is now being exploited for the treatment of some forms of human cancer. However, weak tumour-associated inflammatory responses and the immune-suppressive function of T cells remain major hurdles to broader effectiveness of tumour immunotherapy . Here we show that, after disruption of the CARMA1-BCL10-MALT1 (CBM) signalosome complex, most tumour-infiltrating T cells produce IFNγ, resulting in stunted tumour growth. Notably, genetic deletion of both or even just one allele of CARMA1 (also known as Card11) in only a fraction of T cells-which avoided systemic autoimmunity-was sufficient to produce this anti-tumour effect, showing that it is not the mere loss of suppressive function but the gain of effector activity by T cells that initiates tumour control. The production of IFNγ by T cells was accompanied by activation of macrophages and upregulation of class I molecules of the major histocompatibility complex on tumour cells. However, tumour cells also upregulated the expression of PD-L1, which indicates activation of adaptive immune resistance . Consequently, blockade of PD-1 together with CARMA1 deletion caused rejection of tumours that otherwise do not respond to anti-PD-1 monotherapy. This effect was reproduced by pharmacological inhibition of the CBM protein MALT1. Our results demonstrate that partial disruption of the CBM complex and induction of IFNγ secretion in the preferentially self-reactive T cell pool does not cause systemic autoimmunity but is sufficient to prime the tumour environment for successful immune checkpoint therapy.

Viruses belonging to the diverse Anelloviridae family represent a major constituent of the commensal human virome. Aside from their widespread prevalence and persistence in humans and their absence of detectable pathologic associations, little is known about the immunobiology of the human anellome. In this study, we employed the Phage ImmunoPrecipitation Sequencing (PhIP-Seq) assay for comprehensive analyses of antibody binding to 56 amino acid long anellovirus peptides. We designed and constructed a large and diverse \"AnelloScan\" T7 phage library comprising more than 32,000 non-redundant peptides representing the ORF1, ORF2, ORF3 and TTV-derived apoptosis-inducing protein (TAIP) sequences of more than 800 human anelloviruses (spanning three genera). We used this library to profile the antibody reactivities of serum samples from 156 subjects. The vast majority of anellovirus peptides were not reactive in any of the subjects tested (n=~28,000; ~85% of the library). Antibody reactive peptides were largely restricted to the C-terminal region of the putative capsid protein, ORF1. To characterize antibody responses to newly acquired anellovirus infections, we screened a longitudinal cohort of matched blood-transfusion donors and recipients. Most transmitted anelloviruses did not elicit detectable antibody reactivity in the recipient (29 out of a total of 40 transmitted anelloviruses) and the remainder demonstrated delayed reactivity (~100-150 days after transfusion). This study represents the first large-scale epitope-level serological survey of the antibody response to the human anellome. Competing Interest Statement TV declares no competing interests. HS, CAA, SMJ, AB, TD, DMN, SD, and NLY are employees of and hold equity interests in Ring Therapeutics. VM is an employee of and holds equity interests in Flagship Pioneering, which also holds an equity interest in Ring Therapeutics. HBL is an inventor on an issued patent (US20160320406A) filed by Brigham and Women's Hospital that covers the use of the VirScan technology, is a founder of ImmuneID, Portal Bioscience and Alchemab, and is an advisor to TScan Therapeutics.