Mammalian non-classical major histocompatibility complex I and its receptors: Important contexts of gene, evolution, and immunity

B. M. Pratheek, Tapas K. Nayak, Subhransu S. Sahoo, Prafulla K. Mohanty1, Soma Chattopadhyay2*, Ntiya G. Chakraborty3*, Subhasis Chattopadhyay* School of Biological Sciences, National Institute of Science Education and Research, 1Department of Zoology, Utkal University, 2 Infectious Disease Biology, Institute of Life Sciences, Bhubaneswar, Odisha, India, 3Department of Medicine, University of Connecticut Health Center, Farmington, USA

Qa-1, Qa-2, HFE and RT1 haplotypes in mouse and rat, respectively. [2][3][4][5][6][7] In this review, we briefly describe the gene organization, a phylogenetic analysis of nonclassical MHC molecules and updates on their immunological interaction with receptors like TCR and CD94/NKG2 on T, NK and natural killer T (NKT) cells. We also discuss their role in the pathological state of some important diseases that are associated with altered host cell immunity, which has implication in the basic and translational research of mammalian immune responses and their regulation. rats they are found in chromosome 17 (locus B1) and 20 (locus p12), respectively [ Figure 1]. [9,10] Classical MHC-I molecules and nonclassical MHC-I are expressed in most of the tissues in modest levels, but these are expressed in high quantities in some neoplastic cells. [11][12][13][14] Nonclassical MHC-Is are known to be evolutionary conserved.
It has been suggested from numerous studies that two alleles of HLA-E (HLA-E*0101 and HLA-E*0103) have minimum polymorphism among all HLAs and are found in high frequencies in Caucasians. [15,16] Among these two alleles, HLA-E*0101 (also known as HLA-E 107R ) is expressed strongly in normal cells and in higher frequency than HLA-E*0103 (HLA-E 107G ). HLA-E*0101 differs from HLA-E*0103 at amino acid position 107 where arginine is replaced by glycine. [16] Mouse MHC complex is known as H-2 complex located on chromosome 17. [6,10] In mice several MHC-Ibs are found in the H-2Q, H-2T, and H-2M regions of MHC, whereas Qa-1b is a mouse MHC-Ib molecule encoded by the T23 gene. [17] It was first identified in peripheral T-cells as a serological determinant and later identified as the previously isolated gene 37. [17] Sequence analysis suggests that there are only four known alleles of Qa-1.
Qa-1b is expressed in the majority of inbred laboratory strains, whereas Qa-1a is expressed in most of other strains. On the other hand, Qa-1c and Qa-1d frequencies are very rare. [18] The ability to induce an allogeneic immune response by Qa-1 defines the function of Qa-1 as an MHC ligand for T-cells, which is not restricted by H-2D or H-2K haplotype. [19] An investigation by Aldrich et al. [20] decipher the cell surface expression of the Qa-1 alloantigens with the help of monoclonal anti-Qa-1 cytotoxic T lymphocyte (CTL) cell lines. It has been found that the expression of Qa-1 is high, similar to class I H-2K/D molecules. Moreover, the Qa-1 determinant modifier (Qdm) has been found to be linked with H-2D gene. It is also observed that Qdm may control over expression of certain CTLs-defined Qa-1 antigenic determinants. [20] Another report also suggests that a majority of alloreactive Qa-1-specific CTL clones recognize a specific Qa-1 bound peptide, which is a derivative leader sequence of H-2D. [21] Several studies in the recent past suggest a key role of Qa-1 in innate immunity. Qa-1 is also reported as a ligand for CD94/ NKG2 receptors in mouse NK cells, NKT cells and some subset of T-cells. [22][23][24][25][26] Accordingly, it appears that other than interaction with TCR; the nonclassical MHCs are important for signaling through CD94/NKG2 receptors to modulate host cell immunity. The role of CD94/ NKG2 receptors in Qa-1 and HLA-E mediated immune responses is discussed in a subsequent section.
In several nonhuman primates, existence of MHC-Ib has been suggested earlier. MHC-G has been described in some nonhuman primates. [27][28][29][30][31] It has been mentioned that in chimpanzee (Pan troglodytes) MHC-Ib is known to be organized in similar way as human MHC-Ib. [32] It has also been described in case of many other nonhuman primate species. [27,[32][33][34][35][36][37] MHC-I genes of New World primates appear to be homologous to HLA-G genes than classical HLA-I genes. [27,28] Mamu-G is ortholog of HLA-G in the rhesus monkey (Macaca mulatta) and it is appeared to be a pseudogene. Another nonclassical MHC-I locus called Mamu-AG is also found to be expressed in the placenta of rhesus monkeys.
Mamu-AG encodes MHC-IA locus-related molecules with all the features of human HLA-G, apart from features like a truncated cytoplasmic domain and limited polymorphism. [31] Phylogenetic study comprising exon 2, closer to human and great apes (Pongids). [30] HLA-E and-F homologues have been described in orangutans and macaques. [36][37][38][39] The orthologs of MHC-E have also been identified in nonhuman primates such as gorillas, chimpanzees, bonobos, and vervet (green) monkeys. [38,40]  is orthologous to HLA-E. [35] Moreover, multiple sequence alignment of MHC-F cDNA sequences of human, chimpanzee, macaque and cotton-top tamarin have shown that in cotton-top tamarin, accumulation of nonsynonymous differences are more than synonymous differences in the peptide binding region of this gene. [37] Analysis of the nucleotide sequences of MHC-H in gorillas and chimpanzees revealed that they have a high degree of homology among their alleles. [41] Phylogenetic analysis of some MHC-I genes of gorilla and chimpanzee along with human, shows the close clustering of Gogo-H*01 (gorilla) and Patr-H*01 (chimpanzee) with HLA-H alleles, indicating close evolutionary relationship between them. [41] The gene and protein sequences [ Figure 2 and Tables  and Table 1].

Involvement of Qa-1/HLA-E and CD94/NKG2 System in Altered Immunity and Diseases
Cellular and molecular basis of Qa-1/HLA-E and CD94/ NKG2 system HLA-E is found to be a ligand for CD94/NKG2A, B and C receptors on NK cells. [42] Moreover, it has been shown that CD94/NKG2A receptor expresses on CD8 + T-cells to induce immune inhibitory effect. [26] NK cells in mouse and human express heteromeric C-type lectin receptors comprising CD94 and NKG2. The NKG2A isoform is expressed more than other isoforms and has immunoreceptor tyrosine-based inhibitory motifs in its cytoplasmic domain, which form heterodimer with CD94 to inhibit NK cell function. [25,43,44] CD94/NKG2C, an activating NK cell receptor of the C-type lectin superfamily, has been found to bind to HLA-E.
Moreover, it noncovalently associates with DNAX-activation protein 12 (DAP12), a membrane receptor containing an immunoreceptor tyrosine-based activating motif (ITAM). [45] NK cells are found to recognize and destroy infected cells through Qa-1/HLA-E and CD94/NKG2 receptors. This "missing-self" phenomenon of NK cells plays a key role in recognizing and destroying abnormal cells. These attributes may facilitate viruses to acquire an important immune escape mechanism deviating host protective immunity. [46,47] Receptor profile of Qa-1/HLA-E and CD94/NKG2 system Evidences in the recent past suggest that HLA-E has a role in restricting the ab TCR bearing subsets of T-cells. [48,49] Qa-1 and HLA-E are functional homologues, which are known to have an exclusive role in the regulation of NK cells. Moreover, it has been found that NKT cells co-express TCR and NK1.1 receptors. [50][51][52][53] Mouse invariant NKT (iNKT) cells that express NK cell receptors and TCR a chain of Va14Ja18 (Va24Ja15 in humans) and a semi variant TCR-b, which are found to be associated with Vb8 (Vb11 in humans), Vb2 and Vb7 receptors. [50][51][52] V a 14 TCR recognizes glycolipid antigens, such as a-galactosylceramide and its analogues presented on MHC-I like molecule CD1d. [51,52,[54][55][56][57][58] iNKT cells are also known to be associated with CD94/ NKG2 receptor subsets for their immunoregulatory role in mammalian immunity. [59] It has been shown that differential co-stimulatory signals can be mediated through CD80/86 and CD40 in antigen-presenting cells interacting with NKT cells expressing CD28 and CD154 respectively. [60] Moreover, these results suggest that CD28-CD80/CD86 and CD40-CD154 co-stimulatory pathways may differentially contribute to regulate Th1 and Th2 associated responses of NKT cells in vivo.

H-Q9
H-Q8   However, the specific role of NKT cells in association to CD94/NKG2 and co-stimulatory responses needs further investigation.

Involvement of Qa-1/HLA-E and CD94/NKG2 system in autoimmune diseases
I t h a s b e e n s u g g e s t e d t h a t i n d u c t i o n o f immunosuppressive CD8 + T-cells may be restricted by MH-Ib/Qa-1 to regulate CD4 + T-cell response. [61,62] Moreover, most of the MHC class Ib molecules along antigen-specific Vb8.2 + CD4 + T-cell response. [64] High CD94/NKG2A expression by T-cells has been demonstrated in remission patients following tumor necrosis factor (TNF) based TNF inhibitor therapy compared to active rheumatoid arthritis. Low CD94/ NKG2A expression has been associated with disease severity following withdrawal of therapy. [65] In systemic lupus erythematosus patients, negative correlation of CD69 with CD94/NKG2A inactivated gd TCR bearing T-cell (gd + T-cell) reveals that down-regulation of CD94/ NKG2A may be due to over-activation of such gd + T-cell. [66]

Involvement of Qa-1/HLA-E and CD94/NKG2 system in infectious diseases
It has been proposed that CD94/NKG2 heterodimers may co-stimulate effector functions of differentiated Th1 cells. [67] There are several reports which show CD94/NKG2 expression is markedly up-regulated on CD8 + T-cells during viral and bacterial infections. [68,69] It has been shown that CD94/NKG2 is capable of hindering the CTL activity against Qa-1 and HLA-E positive cells [43] and recently it has been proposed that it may be involved in attenuation of activation induced cell death, which may possibly help in CD8 + T-cell survival during Listeria monocytogenes infection. [70] Several reports on the role of MHC-Ib for viral diseases are available. [71][72][73] MHC-Ib like HLA-G is found to be over-expressed or up-regulated in immune cells, which is found to be immune suppressive in nature during viral infections. In some viruses like human cytomegalovirus infection, HLA-G is found to be down-regulated by viral US10 protein, unlike classical HLAs. [74] However, nonclassical MHC-I, such as HLA-G is found to be resistant to HIV Nef protein mediated cell surface down-regulation. [75] Involvement of Qa-1/HLA-E and CD94/NKG2 system in cancer, immune privilege and altered immunity Association of CD94/NKG2 receptors is found in several cancers, where CD94/NKG2A receptors are found to be widely expressed in tumor infiltrating T-cells.
They are found to be involved in blocking tumor lytic activity. [76] In cervical cancer, it has been reported that CD94/NKG2A receptors are up-regulated in tumor infiltrating T-cells compared to normal cervix. This is also found to be correlated with secretion of cytokines like transforming growth factor-beta and interlukin-15 by cervical cancer, which may elevate the CD94/NKG2A receptors. [77] Moreover, it has been shown that Interferon gamma treatment may protect ovarian carcinoma cell lines from CTL lysis through human nonclassical MHC-Is and CD94/NKG2A-dependent mechanism. [78] In a study with ocular anterior chamber associated  Table 3 and Figure 3]. [79] Moreover, it has been shown that compatibility of Qa-1 haplotype between CD8 + Tregs cells and the immunized recipients is a prerequisite for CD8 + Tregs to suppress the expression of antigen-specific DTH in the recipient mice. [80] The expression of Qa-2, a nonclassical MHC-Ib, has been reported in the corneal endothelium and other substructure lining of the ocular anterior chamber, which suggests that Qa-2 protein may also contribute to the immune-privileged status of the mammalian eye. [81] gestation, but not of later stages. [99] HLA-F is found to interact with ILT-2 and ILT-4, which expressed on the surface of monocytes and CD19 + B cells, but not on CD56 + NK cells or CD3 + T-cells. [100] In tumors such as malignant larynx lesions, HLA-G expression is elevated in benign and premalignant lesions and is reduced in invasive carcinomas and in associated draining cervical lymph nodes. However, HLA-E expression was found to be elevated with increased lesion grade, suggesting the expression of HLA-G as an indicator of tumor invasiveness in malignant laryngeal lesions. [101] In ovarian cancer, it is found that the expression of HLA-E plays an important role in neutralizing CTL infiltration. Low expression of HLA-E is found to be associated with enhanced survival rate. [102] Recently, in the mouse B16 melanoma tumor model, it has been showed that activation of CD4 + Foxp3 − T-cells enable melanoma metastasis, which is mediated by Qa-1 dependent suppression of NK-cell cytotoxicity. [103] Summary and Future Perspective