Novel nonclassical MHC class Ib genes associated with CD8 T cell development and thymic tumors

Abstract

In jawed vertebrates, the heterogeneous nonclassical MHC class Ib (class Ib) gene family encodes molecules structurally similar to classical MHC class Ia (class Ia) but with more limited tissue distribution and lower polymorphism. In mammals, class Ib gene products are involved in stress responses, malignancy and differentiation of intrathymic CD8 T cells. The frog Xenopus laevis possesses at least 20 class Ib genes (XNCs), and 9 subfamilies have been defined so far. We have characterized two novel subfamilies, XNC10 and XNC11. XNC10 is phylogenetically and structurally distinct from both class Ia and other XNC genes. Besides thymic lymphoid tumors, XNC10 is preferentially expressed by circulating T cells and thymocytes of the CD8 lineage both in adult and in larvae from the onset of thymus organogenesis. XNC11 is expressed only by thymocytes and upregulated by several thymic lymphoid tumors. These data provide the first evidence of the expression of any class Ib genes in Xenopus larvae, and suggests evolutionary relationships between certain class Ib genes, malignancy and CD8 T cell ontogeny.

Nonclassical MHC class I-dependent invariant T cells are evolutionarily conserved and prominent from early development in amphibians

“…S1). We selected XNC10 because of its high degree of evolutionary conservation and its early expression in the developing thymus (14). Flow cytometry analysis of splenic leukocytes from naïve adult frogs revealed two distinct XNC10-T-reactive lymphocyte populations that we classified as types I and II based on differences in phenotype and TCR repertoire (Fig.…”

“…Unlike adult frogs, where cell surface class Ia molecules are ubiquitously expressed, larvae have weak and limited class I surface protein expression until the onset of metamorphosis (10-13). Because class Ib gene expression, specifically XNC10, is detected from early thymus organogenesis, class Ib expression has been postulated to compensate for the low class Ia expression during early ontogeny (14). To investigate this possibility, we first determined whether XNC10-T + -reactive cells were present in the spleens of premetamorphic tadpoles (stage 53, 25-26 d postfertilization) by flow cytometry.…”

“…Notably, although both larvae and adults are immunocompetent and have CD8 + T cells, the larval thymus lacks significant class Ia protein expression until metamorphosis (13). Conversely, certain class Ib genes are expressed in tadpoles at the onset of thymic organogenesis (14). This expression pattern and the unusually high conservation of certain Xenopus class Ib genes (15) have prompted us to determine whether these class Ib molecules are involved in amphibian iT cell development.…”

“…The Xenopus nonclassical gene (XNC) class Ib gene XNC10 is one of X. laevis 30 XNC genes (14)(15)(16). XNC10 represents a unique class Ib monogenic lineage phylogenetically distinct from both X. laevis class Ia and other XNC genes but highly conserved among divergent Xenopus species and characterized by interspecies sequence conservation in its putative antigen binding domain (15).…”

“…XNC10 represents a unique class Ib monogenic lineage phylogenetically distinct from both X. laevis class Ia and other XNC genes but highly conserved among divergent Xenopus species and characterized by interspecies sequence conservation in its putative antigen binding domain (15). Additionally, the XNC10 gene is preferentially expressed by thymocytes as early as 3 d postfertilization (14). We hypothesized that XNC10 is critically involved in Xenopus iT cell biology.…”