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

Abstract

Human and murine MHC nonclassical class Ib-restricted invariant T (iT) cell subsets, such as invariant natural killer T cells (iNKT) and mucosal-associated invariant T cells, have specialized functions early in immune responses, especially in modulating subsequent adaptive immune responses. Here, we characterize a prominent iT population in the amphibian Xenopus laevis and show the requirement of the class Ib molecule, Xenopus nonclassical gene 10, in its differentiation and function. Using Xenopus nonclassical gene 10 tetramers and RNAi loss of function by transgenesis, we identified a large class Ib-dependent CD8 − /CD4 − iT subset in unmanipulated frogs and tadpoles. This population is critical for antiviral immunity during early larval stages when classical MHC class Ia function is suboptimal. Furthermore, in young tadpoles with low class Ia expression, deep sequencing revealed additional preponderant invariant T cell receptor (TCR)α rearrangements, implying other iT cell subsets and a predominant selection process mediated by other class Ib molecules. The restriction and requirement of class Ib molecules for development and antiviral immunity of a mammalian iNKT or mucosal-associated invariant T cell counterpart in the amphibian Xenopus show the importance of iT cells in the emergence and evolution of the adaptive immune system.

Dynamics of Individual T Cell Repertoires: From Cord Blood to Centenarians

“…Multiple studies have been performed in recent years to characterize TCR repertoires either in general (13)(14)(15)(16)(17)(18)(19)(20)(21)(22) or at the level of functional T cell subsets (17,18,(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). However, these new opportunities have also brought new hidden pitfalls, which have not always been predicted, recognized, and proportionally addressed in the works published to date.…”

Quantitative Profiling of Immune Repertoires for Minor Lymphocyte Counts Using Unique Molecular Identifiers

“…These methods enabled researchers to decipher the intimate architecture of immune repertoires in health and disease, both at the general scale (1)(2)(3)(4)(10)(11)(12)(13)(14)(15)(16)(17) and in diverse lymphocyte subpopulations, such as naive and memory T cells (10,11,18), functional subsets of CD4 + T cells (19,20) or B cells (5,8), NKT and mucosal-associated invariant T cells subsets (21)(22)(23), tumor-infiltrating lymphocytes (24,25), tissue-specific lymphocytes (26), or Ag-specific T cells (20).…”

Ranavirus Host Immunity and Immune Evasion

“…It is intriguing that, as described above, while Xenopus larvae are naturally MHC class Ia defi cient (Du Pasquier et al 1989 ), they express a number of nonclassical class Ib genes (XNCs), with some of these, such as XNC10 displaying preferential thymic expression (Goyos et al 2009(Goyos et al , 2011. Notably, we have recently identifi ed a prominent X. laevis iT immune cell subset, which requires XNC10 for both its development and function (Edholm et al 2013 ). Using an XNC10 tetramer as well as reverse genetics combining transgenesis and RNA interference, we determined that this iT cell population is CD8 − /CD4 − , expresses a semi-invariant T cell receptor consisting of an invariant TCRα (iVα6-Jα1.43) combined with a limited TCRβ repertoire, and fails to develop in the absence of, or with diminished, XNC10 expres sion (Edholm et al 2013 ).…”

“…Notably, we have recently identifi ed a prominent X. laevis iT immune cell subset, which requires XNC10 for both its development and function (Edholm et al 2013 ). Using an XNC10 tetramer as well as reverse genetics combining transgenesis and RNA interference, we determined that this iT cell population is CD8 − /CD4 − , expresses a semi-invariant T cell receptor consisting of an invariant TCRα (iVα6-Jα1.43) combined with a limited TCRβ repertoire, and fails to develop in the absence of, or with diminished, XNC10 expres sion (Edholm et al 2013 ). Notably, transgenic animals with effectively RNAisilenced thymic and splenic XNC10 expression failed to develop this iT cell subset.…”

“…Notably, transgenic animals with effectively RNAisilenced thymic and splenic XNC10 expression failed to develop this iT cell subset. Moreover, they were also signifi cantly more susceptible to, and more readily succumbed to, FV3 infections (Edholm et al 2013 ) suggesting that these cells are important in anti-ranaviral defenses. It is noteworthy that deep sequencing analysis of tadpole TCRα revealed that Xenopus larvae possess several additional predominant iT cell populations (Edholm et al 2013 ), which are presumably XNC-restricted and most likely participate in immune responses such as those against ranaviruses.…”