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T Cell Receptor (TCR) antigen binding underlies a key mechanism of the adaptive immune response yet the vast diversity of TCRs and the complexity of protein interactions limits our ability to build useful low dimensional representations of TCRs. To address the current limitations in TCR analysis we develop a capacity-controlled disentangling variational autoencoder trained using a dataset of approximately 100 million TCR sequences, that we name TCR-VALID. We design TCR-VALID such that the model representations are low-dimensional, continuous, disentangled, and sufficiently informative to provide high-quality TCR sequence de novo generation. We thoroughly quantify these properties of the representations, providing a framework for future protein representation learning in low dimensions. The continuity of TCR-VALID representations allows fast and accurate TCR clustering and is benchmarked against other state-of-the-art TCR clustering tools and pre-trained language models. Relating T cell receptor (TCR) sequencing to antigen specificity is a challenge especially when TCR specificity is unclear. Here the authors use a low dimensional generative approach to model TCR sequence similarity and to associate TCR sequences with the same specificity.

Host defense against the intracellular pathogen Listeria monocytogenes (Lm) requires innate and adaptive immunity. Here, we directly imaged immune cell dynamics at Lm foci established by dendritic cells in the subcapsular red pulp (scDC) using intravital microscopy. Blood borne Lm rapidly associated with scDC. Myelomonocytic cells (MMC) swarmed around non-motile scDC forming foci from which blood flow was excluded. The depletion of scDC after foci were established resulted in a 10-fold reduction in viable Lm, while graded depletion of MMC resulted in 30-1000 fold increase in viable Lm in foci with enhanced blood flow. Effector CD8+ T cells at sites of infection displayed a two-tiered reduction in motility with antigen independent and antigen dependent components, including stable interactions with infected and non-infected scDC. Thus, swarming MMC contribute to control of Lm prior to development of T cell immunity by direct killing and sequestration from blood flow, while scDC appear to promote Lm survival while preferentially interacting with CD8+ T cells in effector sites.

A central mechanism of tumour progression and metastasis involves the generation of an immunosuppressive ‘macroenvironment’ mediated in part through tumour-secreted factors. Here we demonstrate that upregulation of the Inhibitor of Differentiation 1 (Id1), in response to tumour-derived factors, such as TGFβ, is responsible for the switch from dendritic cell (DC) differentiation to myeloid-derived suppressor cell expansion during tumour progression. Genetic inactivation of Id1 largely corrects the myeloid imbalance, whereas Id1 overexpression in the absence of tumour-derived factors re-creates it. Id1 overexpression leads to systemic immunosuppression by downregulation of key molecules involved in DC differentiation and suppression of CD8 T-cell proliferation, thus promoting primary tumour growth and metastatic progression. Furthermore, advanced melanoma patients have increased plasma TGFβ levels and express higher levels of ID1 in myeloid peripheral blood cells. This study reveals a critical role for Id1 in suppressing the anti-tumour immune response during tumour progression and metastasis. Tumour progression is promoted by the generation of an immunosuppressive macroenvironment. Here, the authors demonstrate that the Inhibitor of Differentiation 1 promotes the switch from dendritic cell differentiation towards myeloid-derived suppressor cell expansion during tumour progression.

T cells survey antigen-presenting dendritic cells (DCs) by migrating through DC networks, arresting and maintaining contact with DCs for several hours after encountering high-potency complexes of peptide and major histocompatibility complex (pMHC), leading to T cell activation. The effects of low-potency pMHC complexes on T cells in vivo , however, are unknown, as is the mechanism controlling T cell arrest. Here we evaluated T cell responses in vivo to high-, medium- and low-potency pMHC complexes and found that regardless of potency, pMHC complexes induced upregulation of CD69, anergy and retention of T cells in lymph nodes. However, only high-potency pMHC complexes expressed by DCs induced calcium-dependent T cell deceleration and calcineurin-dependent anergy. The pMHC complexes of lower potency instead induced T cell anergy by a biochemically distinct process that did not affect T cell dynamics.

Relatively few studies have used live tissue microscopy to evaluate how the immune system responds to pathogens. In this commentary we discuss the challenges of imaging infectious processes and the questions that can be addressed with these dynamic approaches.

T cells play a major role in the adaptive immune response to infection for efficient clearance and protective immunity from most pathogens. T cells must be primed by professional antigen presenting cells (APC), frequently dendritic cells (DC), to become activated. T-APC interactions occur in lymphoid tissue where T cells are highly motile. Activation of the T cell receptor by cognate antigen triggers arrest in motility to allow stable and specialized contact with the APC, termed the immunological synapse. Signaling that initiates and maintains stable T-APC contact has yet to be fully characterized. We employed intravital microscopy to image lymphocyte dynamics in the spleen, a major secondary lymphoid organ important for clearance of blood borne pathogens. We directly image a DC network in the subcapsular red pulp (scDC) where effector T cells migrate and arrest acutely in response to antigen. scDC internalized intravascular Listeria monocytogenes (Lm), an intracellular bacteria. Myelomonocytic cells were recruited and interdigitated with non-motile infected scDC as dynamic swarms and tight foci to contain Lm. Effector CD8+ T cells displayed a two-tiered reduction in motility with antigen independent and dependent components, including stable interactions with infected and noninfected scDC. In addition, we monitored antigen induced intracellular calcium ([Ca2+]i) elevation in vivo. While [Ca2+]i elevation is sufficient to arrest crawling T cells, blocking [Ca2+ ]i elevation did not inhibit arrest in response to antigen. These data suggest there is an alternative antigen induced stopping pathway that allows stable T-APC contacts in the absence of [Ca2+] i elevation. This data has implications for in vivo T cell activation and development of anergy and autoimmunity.