Diverse roles of non-diverse molecules: MHC class Ib molecules in host defense and control of autoimmunity

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While the prime function of classical MHC class I molecules (MHC-I) is to present peptide antigens to pathogen-specific cytotoxic T cells, non-classical MHC-I antigens perform a diverse array of functions in both innate and adaptive immunity. In this review we summarize recent evidence that non classical MHC-I molecules are not only recognized by pathogen-specific T cells but that they also serve as immunoregulatory molecules by stimulating a number of distinct non-conventional T cell subsets.

Introduction

The highly polymorphic ‘classical’ or ‘class Ia’ MHC molecules serve an integral role in adaptive immunity by presenting peptides to cytotoxic T cells. However, there are also a number of ‘non-classical’ or ‘class Ib’ MHC molecules that, while structurally similar to class Ia molecules, frequently have quite distinct functions. Class Ib molecules are typically far less polymorphic than their classical counterparts, can have a more limited pattern of expression and in some cases bind non-peptide ligands (for a review see [1]). MHC class Ib molecules have a diverse range of functions, including in the presentation of lipid antigens (CD1d) for recognition by natural killer T (NKT) cells, as ligands (MR1) for mucosal-associated invariant T (MAIT) cells and serving as dual ligands for both NK cell and αβ T cell receptors (HLA-E and Qa-1b). A rapidly expanding body of literature highlights the diverse roles played by class Ib molecules in pathogen recognition, virus-induced immunopathology, tumor immunosurveillance and regulation of autoimmunity. Here, we summarize recent key work in these areas.

Section snippets

MHC class Ib as innate pathogen recognition molecules

Specific MHC class Ib molecules serve as ligands for T cells expressing ‘semi-invariant’ T cell receptors (TCR). These cells operate early in the course of an immune response and may modulate the subsequent differentiation of the adaptive response [1, 2]. From this perspective, these MHC Ib-restricted T cells constitute components of the cellular innate immune response and their TCRs may arguably be regarded as pattern recognition receptors.

The non-MHC encoded CD1d molecule can present lipid

Adaptive immune recognition of MHC class Ib molecules

Although a number of MHC class Ib molecules are ligands for receptors expressed by innate immunocytes, recent literature points toward an important role for these molecules in adaptive immune responses to pathogens. Class Ib-restricted αβ TCR-expressing CD8 T cells have been identified as participants in the overall adaptive T cell response in a number of mouse disease models [28, 29, 30], and have been shown to be protective in vivo in the case of Qa-1b-restricted and H2-M3-restricted

Qa-1b/HLA-E: double duty MHC class Ib molecules

As ligands for both inhibitory and activating receptors, Qa-1b and its human ortholog HLA-E have diverse immunological roles (Figure 1). The peptide-binding groove of Qa-1b is predominantly occupied by the highly conserved Qa-1b determinant modifier (Qdm) 9mer peptide that is derived from the signal sequence of class Ia molecules [41, 42]. The Qdm:Qa-1b complex is the ligand for CD94-NKG2A [43] an inhibitory signaling receptor on NK cells and CD8 T cells, as well as activating receptors such as

Conclusions

In summary, it is increasingly evident that MHC class Ib molecules can act as restricting elements for effector T cells which can limit the spread of pathogens. Consequently, given the limited polymorphism in these genes, particularly in humans, pathogen-derived peptides that bind these molecules may represent attractive vaccine candidates. However, molecules such as CD1d, MR1, HLA-E and Qa-1b also appear to have distinct roles in immunity through the stimulation of specialized T cell

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgments

This work was supported by NIH grants R01 CA139220 and R01 CA71971 (AEL), and by the National Health and Medical Research Council (NHMRC). LCS is supported by a NHMRC Career Development Award.

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