Positive selection of MHC class Ib-restricted CD8(+) T cells on hematopoietic cells

Department of Immunology and Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
Nature Immunology (Impact Factor: 20). 09/2002; 3(8):772-9. DOI: 10.1038/ni814
Source: PubMed


Unlike conventional CD8(+) T cells, major histocompatibility complex (MHC) class Ib-restricted CD8(+) T cells show an activated phenotype in uninfected mice and respond rapidly to foreign invaders. The underlying factors that contribute to these differences are not well understood. We show here that the activated phenotype of MHC class Ib-restricted CD8(+) T cells was partially acquired as a result of interactions in the thymus and reflected an increased capacity to be selected via interactions with MHC molecules on hematopoietic cells. Using bone marrow-chimeric mice, we have shown that MHC class Ib-restricted, but not MHC class Ia-restricted, CD8(+) T cells specific for Listeria monocytogenes were efficiently selected when MHC class I was expressed only on hematopoietic cells. Thus, the distinct functional properties of MHC class Ib-restricted versus MHC class Ia-restricted CD8(+) T cells may result, at least in part, from the different ways in which they are positively selected in the thymus.

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Available from: Kevin B Urdahl
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    • "During this process, thymic epithelial cells interact with DP cells to determine the fate of immature thymocytes by orchestrating positive and negative selection (4–7). By contrast, homotypic DP–DP interactions drive development and selection of the so-called innate αβ T lymphocytes, which include natural killer T (NKT) and innate CD8+ T cells (8–10). During development in the thymus, as well as in the effector phase in the periphery, NKT and innate CD8+ T cells, which have a restricted TCR repertoire, interact with different non-classical MHC class I molecules (11–14). "
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    ABSTRACT: Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) plays an essential role in the immune system mediating the function of several members of the SLAM family (SLAMF) of receptors, whose expression is essential for T, NK, and B-cell responses. Additionally, the expression of SAP in double-positive thymocytes is mandatory for natural killer T (NKT) cells and, in mouse, for innate CD8(+) T cell development. To date, only two members of the SLAMF of receptors, Slamf1 and Slamf6, have been shown to positively cooperate during NKT cell differentiation in mouse. However, it is less clear whether other members of this family may also participate in the development of these innate T cells. Here, we show that Slamf[1 + 6](-/-) and Slamf[1 + 5 + 6](-/-) B6 mice have ~70% reduction of NKT cells compared to wild-type B6 mice. Unexpectedly, the proportion of innate CD8(+) T cells slightly increased in the Slamf[1 + 5 + 6](-/-) , but not in the Slamf[1 + 6](-/-) strain, suggesting that Slamf5 may function as a negative regulator of innate CD8(+) T cell development. Accordingly, Slamf5(-/-) B6 mice showed an exclusive expansion of innate CD8(+) T cells, but not NKT cells. Interestingly, the SAP-independent Slamf7(-/-) strain showed an expansion of both splenic innate CD8(+) T cells and thymic NKT cells. On the other hand, and similar to what was recently shown in Slamf3(-/-) BALB/c mice, the proportions of thymic promyelocytic leukemia zinc finger (PLZF(hi)) NKT cells and innate CD8(+) T cells significantly increased in the SAP-independent Slamf8(-/-) BALB/c strain. In summary, these results show that NKT and innate CD8(+) T cell development can be regulated in a SAP-dependent and -independent fashion by SLAMF receptors, in which Slamf1, Slamf6, and Slamf8 affect development of NKT cells, and that Slamf5, Slamf7, and Slamf8 affect the development of innate CD8(+) T cells.
    Full-text · Article · Apr 2014 · Frontiers in Immunology
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    • "The innate-like phenotype of CD8 T cells appeared to be a consequence of a selection process similar to that used by invariant natural killer (iNK) T cells and some other innate-like T cell lineages that involves the SLAM associated adapter protein (SAP) (Bendelac et al., 2007; Detre et al., 2010). iNKT cells, in contrast to conventional thymocytes, are selected by glycolipids presented on CD1d molecules expressed on hematopoietic cells (Bendelac et al., 2007; Coles and Raulet, 2000; Urdahl et al., 2002). An innate-like CD4 population was described in mice expressing the MHC class II activator transcription factor (CIITA) in CD4 + thymocytes further implicating selection on DP thymocytes as a requirement for development of innate-like characteristics (Li et al., 2005; Li et al., 2007b). "
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    ABSTRACT: CD8(+) T cells are selected via low-affinity interaction with MHC class I molecules on thymic epithelial cells (TECs). However, compromised T cell receptor signaling was proposed to force CD8(+) T cell selection on hematopoietic cells through a SLAM-associated protein (SAP)-dependent mechanism similar to NKT cells. The outcome is an unconventional CD8(+) T cell with phenotypic and functional characteristics of innate lymphocytes. Here we showed that Id3(-/-) CD8(+) T cells had an innate-like phenotype and required SAP for their development. However, like conventional CD8(+) T cells, Id3(-/-) CD8(+) thymocytes were selected on TECs. The requirement for SAP and the innate-like phenotype was not intrinsic to Id3(-/-) CD8(+) thymocytes. Rather, an expanded population of NKT-like cells induced the innate phenotype on CD8(+) T cells through production of interleukin-4. Our findings reveal that accumulation of NKT-like cells promotes conventional CD8(+) thymocytes to acquire innate lymphocyte characteristics.
    Preview · Article · Aug 2010 · Immunity
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    • "In mice, there are several examples of thymic T cells being selected on class Ib molecules expressed by haematopoietic cells, in the absence of class Ia. For example, in bone marrow-chimeric mice, class Ib-restricted CD8 T cells are efficiently selected only when class Ib is expressed on hematopoietic cells (Urdahl et al, 2002). Additionally, our FACS cell sorting of larval thymocytes shows that XNC10 is expressed by subsets of immature and mature CD8 thymocytes. "
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    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.
    Full-text · Article · Mar 2009 · Molecular Immunology
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