Following solid organ transplantation, small precursor populations of polyclonal CD8+ T cells specific for any graft-expressed antigen preferentially expand their high-affinity clones. This ...phenomenon, termed “avidity maturation,” results in a larger population of CD8+ T cells with increased sensitivity to alloantigen, posing a greater risk for graft rejection. Using a mouse model of minor-mismatched skin transplantation, coupled with the tracking of 2 skin graft-reactive CD8+ T cell receptor-transgenic tracer populations with high and low affinity for the same peptide-major histocompatibility complex, we explored the conventional paradigm that CD8+ T cell avidity maturation occurs through T cell receptor affinity-based competition for cognate antigen. Our data revealed “interclonal CD8-CD8 help,” whereby lower/intermediate affinity clones help drive the preferential expansion of their higher affinity counterparts in an interleukin-2/CD25-dependent manner. Consequently, the CD8-helped high-affinity clones exhibit greater expansion and develop augmented effector functions in the presence of their low-affinity counterparts, correlating with more severe graft damage. Finally, interclonal CD8-CD8 help was suppressed by costimulation blockade treatment. Thus, high-affinity CD8+ T cells can leverage help from low-affinity CD8+ T cells of identical specificity to promote graft rejection. Suppressing provision of interclonal CD8-CD8 help may be important to improve transplant outcomes.
Solid organ transplant recipients show heterogeneity in the occurrence and timing of acute rejection episodes. Understanding the factors responsible for such variability in patient outcomes may lead ...to improved diagnostic and therapeutic approaches. Rejection kinetics of transplanted organs mainly depends on the extent of genetic disparities between donor and recipient, but a role for environmental factors is emerging. We have recently shown that major alterations of the microbiota following broad-spectrum antibiotics, or use of germ-free animals, promoted longer skin graft survival in mice. Here, we tested whether spontaneous differences in microbial colonization between genetically similar individuals can contribute to variability in graft rejection kinetics.
We compared rejection kinetics of minor mismatched skin grafts in C57BL/6 mice from Jackson Laboratory (Jax) and Taconic Farms (Tac), genetically similar animals colonized by different commensal microbes. Female Tac mice rejected skin grafts from vendor-matched males more quickly than Jax mice. We observed prolonged graft survival in Tac mice when they were exposed to Jax mice microbiome through co-housing or fecal microbiota transplantation (FMT) by gastric gavage. In contrast, exposure to Tac mice did not change graft rejection kinetics in Jax mice, suggesting a dominant suppressive effect of Jax microbiota. High-throughput sequencing of 16S rRNA gene amplicons from Jax and Tac mice fecal samples confirmed a convergence of microbiota composition after cohousing or fecal transfer. Our analysis of amplicon data associated members of a single bacterial genus, Alistipes, with prolonged graft survival. Consistent with this finding, members of the genus Alistipes were absent in a separate Tac cohort, in which fecal transfer from Jax mice failed to prolong graft survival.
These results demonstrate that differences in resident microbiome in healthy individuals may translate into distinct kinetics of graft rejection, and contribute to interpersonal variability in graft outcomes. The association between Alistipes and prolonged skin graft survival in mice suggests that members of this genus might affect host physiology, including at sites distal to the gastrointestinal tract. Overall, these findings allude to a potential therapeutic role for specific gut microbes to promote graft survival through the administration of probiotics, or FMT.
Inhibition of CDK8 and CDK19 can convert both naïve and antigen‐experienced TCR‐stimulated T cells into Tregs in a TGFβ‐independent mechanism and in the presence of inflammatory cytokines.
Teamwork by IL‐10+ and IL‐35+ Tregs McIntosh, Christine M.; Alegre, Maria‐Luisa
American journal of transplantation,
August 2019, 2019-08-00, 20190801, Volume:
19, Issue:
8
Journal Article
Peer reviewed
Open access
Distinct populations of IL‐10– and IL‐35–producing Treg cells in the tumor microenvironment cooperatively promote upregulation of BLIMP1 and exhaustion of tumor‐infiltrating conventional T cells.
Regular exercise reduces risk of various chronic diseases and can prevent the development and recurrence of cancer, making it a promising nonpharmacological modulator of disease. Yet the effect of ...regular exercise on solid organ transplant outcome remains uncertain. Using a model of voluntary wheel‐running exercise and skin transplantation in mice, we hypothesized that exercise strengthens the alloimmune response, leading to an increased rate of rejection. Instead, we found that regular exercise in mice resulted in prolonged graft survival, with mean allograft survival time increasing by almost 50%. We observed this graft survival extension in exercised mice despite evidence of a slightly enhanced alloimmune response, comprised of increased proliferation of alloreactive CD4+ T cells, as well as increased interferon‐γ production by these cells. Exercise was not associated with significant changes in numbers of conventional CD4+ or CD8+ T cells, NK cells, or Foxp3+ regulatory T cells. In conclusion, our study suggests that exercise increases skin graft resistance to a similar or slightly higher level of alloimmunity and supports regular exercise as an important beneficial pursuit for transplant recipients.
Voluntary running promotes skin allograft survival in mice.
Oral antigen exposure is a powerful, non‐invasive route to induce immune tolerance to dietary antigens, and has been modestly successful at prolonging graft survival in rodent models of ...transplantation. To harness the mechanisms of oral tolerance for promoting long‐term graft acceptance, we developed a mouse model where the antigen ovalbumin (OVA) was introduced orally prior to transplantation with skin grafts expressing OVA. Oral OVA treatment pre‐transplantation promoted permanent graft acceptance and linked tolerance to skin grafts expressing OVA fused to the additional antigen 2W. Tolerance was donor‐specific, as secondary donor‐matched, but not third‐party allografts were spontaneously accepted. Oral OVA treatment promoted an anergic phenotype in OVA‐reactive CD4+ and CD8+ conventional T cells (Tconvs) and expanded OVA‐reactive Tregs pre‐transplantation. However, skin graft acceptance following oral OVA resisted partial depletion of Tregs and blockade of PD‐L1. Mechanistically, we revealed a role for the proximal gut draining lymph nodes (gdLNs) in mediating this effect, as an intestinal infection that drains to the proximal gdLNs prevented tolerance induction. Our study extends previous work applying oral antigen exposure to transplantation and serves as proof of concept that the systemic immune mechanisms supporting oral tolerance are sufficient to promote long‐term graft acceptance.
Oral introduction of donor antigen, in combination with a regimen designed to improve intestinal lymphatic drainage to increase the bioavailability and duration of antigen exposure, promotes donor‐specific tolerance to minor‐mismatched skin grafts in mice.
Summary
T‐cell lymphomas (TCL) are aggressive lymphomas usually treated with CHOP (cyclophsophamide, doxorubicin, vincristine, prednisolone)‐like regimens upfront. Recent data suggest that TCL are ...driven by epigenetic defects, potentially rendering them sensitive to epigenetic therapies. We explored the therapeutic merits of a combined epigenetic platform using histone deacetylase inhibitors (HDACIs) and DNA methyltransferase inhibitors (DNMT) in in vitro and in vivo models of TCL. The 50% inhibitory concentration (IC50) values revealed romidepsin was the most potent HDACI, with an IC50 in the low nanomolar range. The combination with a hypomethylating agent produced synergy across all cell lines, which was confirmed in cytotoxicity and apoptosis assays. An in vivo xenograft study demonstrated inhibition of tumour growth in the combination cohort compared to the single agent. Gene expression array and global methylation profiling revealed differentially expressed genes and modulated pathways for each of the single treatment conditions and the combination. Most of the effects induced by the single agent treatment were maintained in the combination group. In total, 944 unique genes were modulated by the combination treatment, supporting the hypothesis of molecular synergism. These data suggest combinations of hypomethylating agents and HDACIs are synergistic in models of TCL, which is supported at the molecular level.
Metabolic Control of T Cell Memory Mcintosh, Christine M.; Alegre, Maria‐Luisa
American journal of transplantation,
August 2018, 2018-Aug, 2018-08-00, 20180801, Volume:
18, Issue:
8
Journal Article
Peer reviewed
Open access
For optimal function upon restimulation, memory CD8+ T cells must increase their aerobic metabolic rate to promote the production of citrate, which can be converted to acetyl‐CoA outside of the ...mitochondrion and may be used as a substrate by histone acetyltransferases.
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