Biology subjects

Heim, T. A.

Publications and source records attributed to Heim, T. A..

5 recordsLinked to original sources

bioRxiv2026

Lymphatic egress recycles tumor-experienced effector CD8 T cells to sustain immune surveillance

Successful anti-tumor immune surveillance depends on stem-like CD8+ T cells that are enriched in tumor-draining lymph nodes (LN), but how they are maintained over time remains poorly understood. Here, we identify a continuous lymphatic circuit that sustains stem-like CD8+ T cells. Using photoconversion to fate-map intratumoral T cells we demonstrate that effector cells exit the tumor microenvironment and migrate back to the draining LN. These tumor-specific, migratory effector T cells avoid chronic antigen stimulation, re-express the transcription factor associated with self-renewal, TCF1, and enter a stem-like state in the LN. Antigen presentation in LNs by dendritic cells drives their proliferation thereby inflating the LN stem-like population. Consequently, maintenance of stem-like T cells and ICB response depends on constitutive lymphatic transport, while LN metastasis compromises the stem-like niche, diminishing ICB response. We, therefore, define a continuous, peripheral lymphatic circuit that recycles tumor-experienced effector T cells to fuel durable, systemic immune surveillance.

immunology↗

bioRxiv2026

The CD8 immgenT framework as a universal reference of mouse CD8 Tαβ cell differentiation states

Mouse CD8+ T cell differentiation has been studied extensively in models of infections and tumors, yet no unified framework spans the full spectrum of immunological contexts. Within the immgenT project, we profiled RNA, surface markers, and TCR clonotypes in conventional CD8+ T cells across >600 samples, spanning multiple perturbations, tissues, and timepoints. Twenty-one clusters across naive, effector, circulating memory, tissue-resident memory, progenitor-exhausted, and terminally-exhausted CD8+ T cell compartments emerged, with striking molecular convergence across acute and chronic infections, tumors, autoimmunity, aging, and homeostasis, illustrating that shared transcriptional states support protective or dysfunctional outcomes depending on developmental history and microenvironment. We validate immgenT as a comprehensive reference by integrating external datasets from conditions not represented in immgenT and by defining a flow cytometry panel spanning the CD8+ T cell landscape. Thus, immgenT-CD8 provides a molecular framework for harmonizing CD8+ T cell literature and clarifies relationships across diverse immune challenges.

immunology↗

bioRxiv2025

T Lymphocyte-Specific Deletion of SHP1 and SHP2 Promotes Activation-Induced Cell Death of CD4+ T Cells and Impairs Antitumor Response

SHP1 (PTPN6) and SHP2 (PTPN11) are closely related protein-tyrosine phosphatases (PTPs), which are autoinhibited until their SH2 domains bind paired tyrosine-phosphorylated immunoreceptor tyrosine-based inhibitory/switch motifs (ITIMs/ITSMs). These PTPs bind overlapping sets of ITIM/ITSM-bearing proteins, suggesting that they might have some redundant functions. By studying T cell-specific single and double knockout mice, we found that SHP1 and SHP2 redundantly restrain naive T cell differentiation to effector and central memory phenotypes, with SHP1 playing the dominant role. Surprisingly, loss of SHP2 alone in T cells enhanced the antitumor effects of anti-PD-1 antibodies, whereas there was no effect of SHP1 deletion. Also unexpectedly, the absence of both PTPs resulted in poorer tumor control and failure to respond to PD-1 blockade, associated with reduced frequency and activation of T cells and dendritic cells. Mechanistic studies revealed that CD4+, but not CD8+ T cells lacking SHP1 and SHP2 show increased activation-induced cell death upon anti-CD3/CD28 stimulation. Adoptive transfer of antigen-specific CD4+ T cells restored normal levels of tumor control in mice lacking both PTPs. Together, our results demonstrate that SHP1 or SHP2 is required to prevent activation-induced cell death of CD4+ T cells and is critical for tumor immunity, raising the possibility that inhibition of SHP2 might augment the therapeutic efficacy of PD-1-based immune therapy. SIGNIFICANCE STATEMENTSHP1 and SHP2 are related protein tyrosine phosphatases that associate with several of the same ITIM/ITSM-containing receptors or T cell receptor (TCR) signaling molecules. The individual roles of SHP1 and SHP2 in T cells have been reported previously, but potentially redundant functions are less well understood. Here we uncover an essential function in CD4+ T cells that is manifest only in the absence of both enzymes and is critical for the control of tumors.

immunology↗

bioRxiv2023

CXCR6 promotes dermal CD8+ T cell survival and transition to long-term tissue residence

Tissue resident memory T cells (TRM) provide protection against local re-infection, and yet the interstitial signals necessary for their formation and persistence remain incompletely understood. Here we show that antigen-dependent induction of the chemokine receptor, CXCR6, is a conserved adaptation to peripheral tissue infiltration that promotes TRM formation after viral infection. Deficient TRM formation in the absence of CXCR6 was not explained by canonical trafficking as CXCR6 was not required for tissue entry, was dispensable for the early accumulation of antigen-specific CD8+ T cells in skin, and did not restrain their exit. Further, single cell sequencing indicated that Cxcr6-/- CD8+ T cells were competent to acquire a transcriptional program of residence and TRM that formed were equally functional compared to their WT counterparts when reactivated greater than 100 days post primary infection. The reduced numbers observed at memory time points, where instead found to associate with impaired redox homeostasis and antioxidant capacity during the transition from effector to memory states. As such, Cxcr6-/- CD8+ T cells exhibited increased rates of apoptosis in the dermis relative to controls, which led to reduced numbers of TRM in the epidermis at memory. CXCR6 therefore promotes the metabolic adaptation of T cells as they engage antigen in tissue to increase the probability of memory differentiation and long-term residence. One Sentence SummaryCXCR6 promotes mechanisms of cellular adaptation to tissue that support local survival and the transition to tissue residence.

immunology↗

bioRxiv2021

Infection-induced dermal lymphatic zippering restricts viral dissemination from skin and promotes anti-viral CD8+ T cell expansion.

Lymphatic vessels are often considered passive conduits that rapidly flush antigenic material, pathogens, and cells to draining lymph nodes. Recent evidence, however, suggests that lymphatic vessels actively regulate diverse processes from antigen transport to leukocyte trafficking and dietary lipid absorption. Here we tested the hypothesis that dermal lymphatic transport is dynamic and contributes to innate host defense during viral infection. We demonstrate that cutaneous vaccinia virus infection activates the tightening of lymphatic interendothelial junctions, termed zippering, in a VEGFA/VEGFR2-dependent manner. Both antibody-mediated blockade of VEGFA/VEGFR2 and lymphatic-specific deletion of Vegfr2 impaired lymphatic capillary zippering and increased fluid flux out of tissue. Strikingly, inhibition of lymphatic zippering allows viral dissemination to draining lymph nodes independent of dendritic cell migration and impairs CD8+ T cell priming. These data indicate that infection-induced dermal lymphatic capillary zippering is a context-dependent, active mechanism of innate host defense that limits interstitial fluid and virion flux and promotes protective, anti-viral CD8+ T cell responses. SummaryCutaneous infection with vaccinia virus induces VEGFR2-dependent dermal lymphatic capillary zippering. This tightening of lymphatic junctions exacerbates tissue edema, sequesters virus, and promotes anti-viral CD8+ T cell responses. Dermal lymphatic capillaries are therefore an active component of innate host defense.

immunology↗