Heterogeneity in allospecific T cell function in transplant-tolerant hosts determines susceptibility to rejection following infection.

Even when successfully induced, immunological tolerance to solid organs remains vulnerable to inflammatory insults, which can trigger rejection. In a mouse model of cardiac allograft tolerance in which infection with Listeria monocytogenes (Lm) precipitates rejection of previously accepted grafts, we showed that recipient CD4+ TCR75 cells reactive to a donor MHC class I-derived peptide become hypofunctional if the allograft is accepted for more than 3 weeks. Paradoxically, infection-induced transplant rejection was not associated with transcriptional or functional reinvigoration of TCR75 cells.

Biological Time Travel: Tracking the Journey of Alloreactive T Cells Through Longitudinal Biobanking.

A significant risk for transplant recipients is the development of tumors. In general, some but not all malignancies are more frequent in transplant hosts due to chronic immunosuppression caused by a compromised immune surveillance. Of additional relevance, checkpoint blockade therapies (CBT) to treat malignancies can also drive transplant rejection.

Reduced Satb1 expression predisposes CD4 T conventional cells to Treg suppression and promotes transplant survival.

Limiting CD4 T cell responses is important to prevent solid organ transplant rejection. In a mouse model of costimulation blockade-dependent cardiac allograft tolerance, we previously reported that alloreactive CD4 conventional T cells (Tconvs) develop dysfunction, losing proliferative capacity. In parallel, induction of transplantation tolerance is dependent on the presence of regulatory T cells (Tregs).

Exploiting immunometabolism and T cell function for solid organ transplantation.

Cellular metabolism is central to T cell function and proliferation, with most of the research to date focusing on cancer and autoimmunity. Cellular metabolism is associated with a host of physiological phenomena, from epigenetic changes, to cellular function and fate. For the purpose of this review, we will discuss the metabolism of T cells relating to their differentiation and function.

A Hypermorphic Allele Contributes to Impaired Thymic Deletion of Autoreactive Diabetogenic CD8 T Cells in NOD Mice.

In both NOD mice and humans, the development of type 1 diabetes (T1D) is dependent in part on autoreactive CD8 T cells recognizing pancreatic β cell peptides presented by often quite common MHC class I variants. Studies in NOD mice previously revealed that the common H2-K and/or H2-D class I molecules expressed by this strain aberrantly lose the ability to mediate the thymic deletion of pathogenic CD8 T cell responses through interactions with T1D susceptibility genes outside the MHC. A gene(s) mapping to proximal chromosome 7 was previously shown to be an important contributor to the failure of the common class I molecules expressed by NOD mice to mediate the normal thymic negative selection of diabetogenic CD8 T cells.

Improved Murine MHC-Deficient HLA Transgenic NOD Mouse Models for Type 1 Diabetes Therapy Development.

Improved mouse models for type 1 diabetes (T1D) therapy development are needed. T1D susceptibility is restored to normally resistant NOD.β2m mice transgenically expressing human disease-associated HLA-A*02:01 or HLA-B*39:06 class I molecules in place of their murine counterparts.