Description of an Ectothermic TCR Coreceptor, CD8α, in Rainbow Trout

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114

117

The T cell coreceptor CD4 is a transmembrane glycoprotein belonging to the Ig superfamily and is essential for cell-mediated immunity. Two different genes were identified in rainbow trout that resemble mammalian CD4. One (trout CD4) encodes four extracellular Ig domains reminiscent of mammalian CD4, whereas the other (CD4REL) codes for two Ig domains. Structural motifs within the amino acid sequences suggest that the two Ig domains of CD4REL duplicated to generate the four-domain molecule of CD4 and the related gene, lymphocyte activation gene-3. Here we present evidence that both of these molecules in trout are homologous to mammalian CD4 and that teleosts encode an additional CD4 family member, lymphocyte activation gene-3, which is a marker for activated T cells. The syntenic relationships of similar genes in other teleost and non-fish genomes provide evidence for the likely evolution of CD4-related molecules in vertebrates, with CD4REL likely representing the primordial form in fish. Expression of both CD4 genes is highest in the thymus and spleen, and mRNA expression of these genes is limited to surface IgM− lymphocytes. consistent with a role for T cell functionality. Finally, the intracellular regions of both CD4 and CD4REL possess the canonical CXC motif involved in the interaction of CD4 with p56LCK, implying that similar mechanisms for CD4+ T cell activation are present in all vertebrates. Our results therefore raise new questions about T cell development and functionality in lower vertebrates that cannot be answered by current mammalian models and, thus, is of fundamental importance for understanding the evolution of cell-mediated immunity in gnathosomes.

Section: T Cell Activation Are Present In All Vertebrates Our Resultmentioning

confidence: 99%

Evolution of the CD4 Family: Teleost Fish Possess Two Divergent Forms of CD4 in Addition to Lymphocyte Activation Gene-3

Laing

Zou

Purcell

et al. 2006

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117

“…Three types of full-length B7 cDNA were isolated from head kidney cDNAs by RACE with specific primers (supplemental Table I) 5 based on predicted B7 DNA sequences. Fugu B7 structures were analyzed with the following programs: SignalP (www.cbs.dtu.dk/services/SignalP) for signal peptide, SOSUI (sosui.proteome.bio.tuat.ac.jp/sosuimenu-0.html) for transmembrane region, and InterPro (www.ebi.ac.uk/interpro/) for Ig-like domains.…”

Section: Animals and Cdna Preparationmentioning

confidence: 99%

Teleost B7 Expressed on Monocytes Regulates T Cell Responses

Sugamata

Suetake

Kikuchi

et al. 2009

In mammals, professional APCs induce adaptive immunity via the activation of T cells. During this process, B7 family molecules present upon APCs are known to play crucial roles in optimal T cell stimulation. In contrast, the confirmation of APCs in a nonmammalian vertebrate has yet to be achieved. To obtain further insights into the evolutionary origin of APCs, we have identified three members of the B7 family in the teleost Takifugu rubripes (fugu): B7-H1/DC, B7-H3, and B7-H4. The three fugu B7s were expressed on the surface of blood monocytes. The B7 ؉ monocytes, which are composed of at least two distinct populations, expressed the MHC class II component gene. The fugu B7 molecules bound to activated T cells, indicating that putative B7 receptors were expressed upon T cells. Fugu B7-H1/DC inhibited T cell proliferation concomitant with increasing levels of both IL-10 and IFN-␥ expression, whereas both B7-H3 and B7-H4 promoted T cell growth following IL-2 induction and the suppression of IL-10. These observations indicate that fugu B7s regulate T cell responses via receptors upon T cells. We suggest that fish B7 ؉ monocytes are APCs and that a costimulatory system has already developed in fish via the evolutionary process.

“…TCR-MHC-peptide interactions induce signaling events through CD3 in mammals and most likely in lower vertebrates because a complete set of CD3 genes, including TCR, CD3⑀, and CD3␥␦, has been found in Pufferfish and Xenopus (39,40). CD8␣ has been identified in rainbow trout (41); however, the cytoplasmic tail lacks the consensus p56 lck motif, suggesting that TCR/CD3/CD8-mediated signaling events may be different in teleosts.…”

mentioning

confidence: 99%

Costimulatory Receptors in a Teleost Fish: Typical CD28, Elusive CTLA4

Bernard

Riteau

Hansen

et al. 2006

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T cell activation requires both specific recognition of the peptide-MHC complex by the TCR and additional signals delivered by costimulatory receptors. We have identified rainbow trout sequences similar to CD28 (rbtCD28) and CTLA4 (rbtCTLA4). rbtCD28 and rbtCTLA4 are composed of an extracellular Ig-superfamily V domain, a transmembrane region, and a cytoplasmic tail. The presence of a conserved ligand binding site within the V domain of both molecules suggests that these receptors likely recognize the fish homologues of the B7 family. The mRNA expression pattern of rbtCD28 and rbtCTLA4 in naive trout is reminiscent to that reported in humans and mice, because rbtCTLA4 expression within trout leukocytes was quickly up-regulated following PHA stimulation and virus infection. The cytoplasmic tail of rbtCD28 possesses a typical motif that is conserved in mammalian costimulatory receptors for signaling purposes. A chimeric receptor made of the extracellular domain of human CD28 fused to the cytoplasmic tail of rbtCD28 promoted TCR-induced IL-2 production in a human T cell line, indicating that rbtCD28 is indeed a positive costimulator. The cytoplasmic tail of rbtCTLA4 lacked obvious signaling motifs and accordingly failed to signal when fused to the huCD28 extracellular domain. Interestingly, rbtCTLA4 and rbtCD28 are not positioned on the same chromosome and thus do not belong to a unique costimulatory cluster as in mammals. Finally, our results raise questions about the origin and evolution of positive and negative costimulation in vertebrate immune systems.