Evolution of the major histocompatibility complex: isolation of class II A cDNA clones from the cartilaginous fish.

Abstract

Along with the T-cell receptor and immunoglobulin, the major histocompatibility complex (MHC) plays a key role in mounting immune responses to foreign antigen. To gain insights into the evolution of the MHC, class II A cDNA clones were isolated from nurse sharks, a member of the class of cartilaginous fish. Two closely related cDNA clones, which might encode allelic products, were identified; of the three amino acid substitutions found in the al domain, two were located at positions postulated to interact with processed peptides. The deduced nurse shark MHC class H a chains showed conspicuous structural similarity to their mammalian counterparts. Isolation of cDNA clones encoding typical MHC class II a chains was unexpected since no direct evidence for T-cellmediated immune responses has been obtained in the cartilaginous fish. The cartilaginous fish is phylogenetically the most primitive class of vertebrates from which any MHC gene has been isolated.Genes of the major histocompatibility complex (MHC) encode two classes of structurally similar, but functionally distinct, glycoproteins that present peptides to T cells (1, 2). In general, MHC class I molecules, consisting of an a chain and ,82-microglobulin, present peptides derived from endogenously synthesized proteins to CD8+ T cells. The peptides are bound by two membrane-distal domains (al and a2), which form a deep cleft made up of an eight-stranded (3-pleated sheet topped by two long a-helices (3, 4). MHC class II molecules are heterodimers that, as a rule, present peptides derived from exogenously acquired proteins to CD4+ T cells. The peptides are bound by two membranedistal domains (al and (31), assumed to form a cleft structurally similar to that of MHC class I molecules (5).At which stage of evolution did an ancestral MHC molecule emerge, and when and how did it diversify into two classes of functionally specialized molecules? Was an ancestral MHC molecule class I-like or class II-like? These questions, which are of fundamental importance in understanding the evolution of immunity (6-8), can be addressed only by studying MHC genes of primitive creatures. In addition, the structure of such MHC genes might provide a clue to the origin of membrane-distal, peptide-binding domains (9) and to the primordial function of MHC molecules. With these points in mind, we have embarked upon a project aimed at isolating MHC genes from primitive vertebrates (10).t

A family of MHC class I-like genes located in the vicinity of the mouse leukocyte receptor complex

“…The primer sequences were 5Ј-TGGCTTGGGATCTTCAAAGT-3Ј (sense) and 5Ј-TCCTCTGTCTTGTTTGGCTGTT-3Ј (antisense) for Mill1 and 5Ј-TTTGCACAAAACTCCATTTGA-3Ј (sense) and 5Ј-AGAAACAGCCAAGCCTCAGTC-3Ј (antisense) for Mill2. The cDNA templates for PCR were synthesized as described (20) by using total cellular RNAs isolated from the skin of 1-day-old BALB͞cCrSlc mice (Mill1) and the lung of adult BALB͞cCrSlc mice (Mill2). PCR products were cloned into the pGEM-T Easy vector (Promega), and their sequences were determined by using an automated sequencer.…”

In vivo Priming of TNP-reactive Effector Cells in Carp.

“…The fact that the spe cific cell-mediated cytotoxicity against TNP-modified autologous cells was induced suggests that cells similar to mammalian CTLs exist in fish. Since the MHC genes (Hashimoto et al, 1990;Kasahara et al, 1992;Okamura et al, 1997;Stet et al, 1998) and T cell recep tor gene (Partula et al, 1994;Rast et al, 1997) …”

T-cell receptor gene homologs are present in the most primitive jawed vertebrates.

“…Although TCR genes have not yet been identified in bony fish, their existence is suggested by the presence of distinct T-cell functions (10,11) and both MHC 1 (12) and MHC II (12,13) genes. MHC genes also have been identified in the more phylogenetically distant cartilaginous fish (14)(15)(16); however, the chronic nature of allograft rejection and lack of other demonstrable T-cell-dependent responses question the existence of a homologous form of T-cell immunity in these species (16,17). The FIG.…”