MHC Class Ia Empowers MHC Class Ib-restricted CD8+ T Cells with Strong Tumoricidal Capacity

The tumoricidal effects of CD8+T cells are well acknowledged, but how MHC Ib-restricted CD8+T (Ib-CD8+T) cells contribute to anti-tumor immunity remains obscure. Here, we show that infusion of MHC Ia+ cells to Kb-/-Db-/- mice induced the expansion of Ib-CD8+T cells in tumors and potently inhibited tumor progression. Such priming of Ib-CD8+T cells by MHC-Ia is not MHC haplotype restricted and MHC Ia tetramers alone can prime Ib-CD8+T cells for activation. The MHC Ia priming promoted Tbet expression in Ib-CD8+T cells and in absence of Tbet, such priming effect diminished. Importantly, these tumoricidal Ib-CD8+T cells are positive for CX3CR1, and exhibit rapid proliferation, high expression of cytotoxic factors, and prolonged persistence at tumor sites. Adoptive transfer of CX3CR1+Ib-CD8+T cells to wild type mice resulted in potent anti-tumor effects. Our findings unravel an uncharacterized function of MHC Ia molecules in immunoregulation and raise the possibility of using Ib-CD8+T cells in tumor immunotherapy.

Short Duration Alagebrium Chloride Therapy Prediabetes Does Not Inhibit Progression to Autoimmune Diabetes in an Experimental Model

Mechanisms by which advanced glycation end products (AGEs) contribute to type 1 diabetes (T1D) pathogenesis are poorly understood. Since life-long pharmacotherapy with alagebrium chloride (ALT) slows progression to experimental T1D, we hypothesized that acute ALT therapy delivered prediabetes, may be effective. However, in female, non-obese diabetic (NODShiLt) mice, ALT administered prediabetes (day 50–100) did not protect against experimental T1D. ALT did not decrease circulating AGEs or their precursors. Despite this, pancreatic β-cell function was improved, and insulitis and pancreatic CD45.1+ cell infiltration was reduced. Lymphoid tissues were unaffected. ALT pre-treatment, prior to transfer of primed GC98 CD8+ T cell receptor transgenic T cells, reduced blood glucose concentrations and delayed diabetes, suggesting islet effects rather than immune modulation by ALT. Indeed, ALT did not reduce interferon-γ production by leukocytes from ovalbumin-pre-immunised NODShiLt mice and NODscid recipients given diabetogenic ALT treated NOD splenocytes were not protected against T1D. To elucidate β-cell effects, NOD-derived MIN6N8 β-cell major histocompatibility complex (MHC) Class Ia surface antigens were examined using immunopeptidomics. Overall, no major changes in the immunopeptidome were observed during the various treatments with all peptides exhibiting allele specific consensus binding motifs. As expected, longer MHC Class Ia peptides were captured bound to H-2Db than H-2Kb under all conditions. Moreover, more 10–12 mer peptides were isolated from H-2Db after AGE modified bovine serum albumin (AGE-BSA) treatment, compared with bovine serum albumin (BSA) or AGE-BSA+ALT treatment. Proteomics of MIN6N8 cells showed enrichment of processes associated with catabolism, the immune system, cell cycling and presynaptic endocytosis with AGE-BSA compared with BSA treatments. These data show that short-term ALT intervention, given prediabetes, does not arrest experimental T1D but transiently impacts β-cell function.

The MHC Class Ia Genes in Chenfu’s Treefrog (Zhangixalus chenfui) Evolved via Gene Duplication, Recombination, and Selection

The molecular mechanisms underlying the evolution of adaptive immunity-related proteins can be deduced by a thorough examination of the major histocompatibility complex (MHC). Currently, in vertebrates, there is a relatively large amount of research on MHCs in mammals and birds. However, research related to amphibian MHC genes and knowledge about the evolutionary patterns is limited. This study aimed to isolate the MHC class I genes from Chenfu’s Treefrog (Zhangixalus chenfui) and reveal the underlying evolutionary processes. A total of 23 alleles spanning the coding region of MHC class Ia genes were identified in 13 individual samples. Multiple approaches were used to test and identify recombination from the 23 alleles. Amphibian MHC class Ia alleles, from NCBI, were used to construct the phylogenetic relationships in MEGA. Additionally, the partition strategy was adopted to construct phylogenetic relationships using MrBayes and MEGA. The sites of positive selection were identified by FEL, PAML, and MEME. In Chenfu’s Treefrog, we found that: (1) recombination usually takes place between whole exons of MHC class Ia genes; (2) there are at least 3 loci for MHC class Ia, and (3) the diversity of genes in MHC class Ia can be attributed to recombination, gene duplication, and positive selection. We characterized the evolutionary mechanisms underlying MHC class Ia genes in Chenfu’s Treefrog, and in so doing, broadened the knowledge of amphibian MHC systems.