Tissue-Specific Transplantation Antigens: Structurally Unique Isoforms of MHC-Related Proteins in Immunologically

The immune network of the small intestine must maintain tolerance to an immense and diverse community of commensal microorganisms and a broad array of dietary antigens while constantly at the ready for insult from a variety of infectious agents. Situated at the front lines of intestinal immune defense are intraepithelial lymphocytes, the largest population of T cells in the body whose functions are only recently beginning to be revealed. Key to unlocking the roles of these unique immune effectors in health and disease is a better understanding of the receptor/ligand interactions that instruct their education, maintenance and reactivity. Many lines of evidence investigating the identity and function of IEL ligands point to molecules of the nonclassical class I major histocompatibility complex. We describe here five nonclassical, or class Ib, MHC - H2-Bl, Tw5, Q1, Q2 and T3 - that are transcriptionally restricted to cells of the intestinal epithelium, in close association with IEL. Canonical and alternatively spliced transcripts of these class Ib MHC encode protein products that can be expressed at the cell surface and nonamer peptides capable of associating with the CD94/NKG2A inhibitory receptor ligand Qa-1. We and others have demonstrated that, in addition to alpha beta and gamma delta TCR, IEL are capable of expressing natural killer cell activating and inhibitory receptors including CD94/NKG2A, NKG2D, Ly49E and Ly49F. Thus, multiple products of gut-restricted class Ib MHC are positioned to associate with class I MHC-engaging T cell and NK cell receptors expressed by IEL. Since the intestine is not the only organ that must balance immune reactivity and tolerance, we wondered if tissue-specific class Ib MHC expressed in other tolerance-associated or immune privileged tissues have similar properties to gut-specific class Ib MHC. We found that liver-restricted Q10 and brain-expressed Q5, like gut-restricted class Ib MHC and human placental HLA-G, are also extensively alternatively spliced and encode nonamer peptides capable of engaging Qa-1. We postulate that these properties of tissue-specific class Ib MHC are critical to MHC-mediated tolerance induction and/or maintenance in tolerance-associated tissues.