Heterogeneity within T Cell Memory: Implications for Transplant Tolerance

Adaptive immunity in both mouse and man results in the generation of immunological memory. Memory T cells are both friend and foe to transplant recipients, as they are intimately involved and in many cases absolutely required for the maintenance of protective immunity in the face immunosuppression, yet from the evidence presented herein they clearly constitute a formidable barrier for the successful implementation of tolerance induction strategies in transplantation. This review describes the experimental evidence demonstrating the increased resistance of memory T cells to many distinct tolerance induction strategies, and outlines recent advances in our knowledge of the ways in which alloreactive memory T cells arise in previously untransplanted individuals. Understanding the impact of alloreactive memory T cell specificity, frequency, and quality might allow for better donor selection in order to minimize the donor-reactive memory T cell barrier in an individual transplant recipient, thus allowing stratification of relative risk of alloreactive memory T cell mediated rejection, and conversely increase the likelihood of successful establishment of tolerance. However, further research into the molecular and cellular pathways involved in alloreactive memory T cell-mediated rejection is required in order to design new strategies to overcome the memory T cell barrier, without critically impairing protective immunity

Expression patterns of a circadian clock gene are associated with age-related polyethism in harvester ants, Pogonomyrmex occidentalis

<p>Abstract</p> <p>Background</p> <p>Recent advances in sociogenomics allow for comparative analyses of molecular mechanisms regulating the development of social behavior. In eusocial insects, one key aspect of their sociality, the division of labor, has received the most attention. Age-related polyethism, a derived form of division of labor in ants and bees where colony tasks are allocated among distinct behavioral phenotypes, has traditionally been assumed to be a product of convergent evolution. Previous work has shown that the circadian clock is associated with the development of behavior and division of labor in honeybee societies. We cloned the ortholog of the clock gene, <it>period</it>, from a harvester ant (<it>Pogonomyrmex occidentalis</it>) and examined circadian rhythms and daily activity patterns in a species that represents an evolutionary origin of eusociality independent of the honeybee.</p> <p>Results</p> <p>Using real time qPCR analyses, we determined that harvester ants have a daily cyclic expression of <it>period </it>and this rhythm is endogenous (free-running under dark-dark conditions). Cyclic expression of <it>period </it>is task-specific; foragers have strong daily fluctuations but nest workers inside the nest do not. These patterns correspond to differences in behavior as activity levels of foragers show a diurnal pattern while nest workers tend to exhibit continuous locomotor activity at lower levels. In addition, we found that foragers collected in the early fall (relative warm, long days) exhibit a delay in the nightly peak of <it>period </it>expression relative to foragers collected in the early spring (relative cold, short days).</p> <p>Conclusion</p> <p>The association of <it>period </it>mRNA expression levels with harvester ant task behaviors suggests that the development of circadian rhythms is associated with the behavioral development of ants. Thus, the circadian clock pathway may represent a conserved 'genetic toolkit' that has facilitated the parallel evolution of age-related polyethism and task allocation in social insects.</p

LCK connects NTB-A and SAP signaling in T cells to restimulation-induced cell death

Signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) is an adaptor protein required for SLAM family receptor signaling. In T cells, signaling from different SLAM receptors (SLAM-Rs) governs differentiation, effector function, and apoptosis specifically through the self-regulatory program of T cell receptor restimulation-induced cell death (RICD). Indeed, SLAM-R signaling and RICD are impaired in X-linked lymphoproliferative disease (XLP) patients that are deficient for SAP, as well as in SAP-deficient mice. Importantly, defective RICD likely contributes to excessive CD8+ T cell accumulation and severe immunopathology noted in XLP patients upon infection with Epstein-Barr Virus (EBV). It is well established that SAP signaling through different SLAM-Rs is associated with the recruitment of the Src-family kinase FYN. Surprisingly, we recently discovered that FYN has no role in RICD. Instead, our data suggests that SAP enhances the recruitment and activation of LCK to the SLAM family receptor NK, T, and B cell Antigen (NTB-A), and thus amplifies TCR signaling for optimal RICD. In this research highlight we review the role of SAP in T cells and describe our recent findings placing LCK as an important player in SAP-mediated NTB-A signaling for T cell apoptosis

Transplantation elicits a clonally diverse CD8+ T cell response that is comprised of potent CD43+ effectors

Summary: CD8+ T cells mediate acute rejection of allografts, which threatens the long-term survival of transplanted organs. Using MHC class I tetramers, we find that allogeneic CD8+ T cells are present at an elevated naive precursor frequency relative to other epitopes, only modestly increase in number after grafting, and maintain high T cell receptor diversity throughout the immune response. While antigen-specific effector CD8+ T cells poorly express the canonical effector marker KLRG-1, expression of the activated glycoform of CD43 defines potent effectors after transplantation. Activated CD43+ effector T cells maintain high expression of the coreceptor induced T cell costimulator (ICOS) in the presence of CTLA-4 immunoglobulin (Ig), and dual CTLA-4 Ig/anti-ICOS treatment prolongs graft survival. These data demonstrate that graft-specific CD8+ T cells have a distinct response profile relative to anti-pathogen CD8+ T cells and that CD43 and ICOS are critical surface receptors that define potent effector CD8+ T cell populations that form after transplantation