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

Abstract

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.

Molecular characterization and expression of CD2 in Nile tilapia (Oreochromis niloticus) in response to Streptococcus agalactiae stimulus

“…The BLAST analysis revealed the overall sequence homology of the CD2 proteins among different species, even among different fish species, was very poor. This finding is consistent with the result of previous studies about other costimulatory molecules in teleost, including CD28 [39,40], CD80/ CD86 [41,42] and CTLA-4 [39]. Fish are the most primitive vertebrates to possess essential components of T-cell immunity, which includes MHC, TCRs, CD3, CD4, CD8, etc, to allow the clonal selection of T-cells [27,28].…”

“…In mammals, CD2 can function as a costimulatory molecule and accelerate production of IL-2, which is the most important cytokine to promote proliferation and differentiation of T-cells [11e15]. Recent progress in evolutionary immunology supports the notion that the capacity to modulate IL-2 expression is a primordial function that has been conserved in both fish and mammals costimulatory molecules [39,41,69], suggesting On-CD2 may also possess similar function to activate T-cells. This hypothesis was supported by distinct kinetic expressions of On-CD2 in the thymus and spleen.…”

Teleost B7 Expressed on Monocytes Regulates T Cell Responses

“…In addition, orphan receptors similar to mammalian costimulatory receptors such as CD28 upon the T cell have been reported in fish species (6,7). These observations suggest that fish species might have APCs and a costimulatory system.…”

Differential virulence mechanisms of infectious hematopoietic necrosis virus in rainbow trout (Oncorhynchus mykiss) include host entry and virus replication kinetics

“…It is possible that transcriptional regulation occurs in the adaptive immune cells very early, even if their functional activity occurs much later in the infection. Downregulation of CD28, occurring simultaneously with the upregulation of CTLA-4, suggested T-cell activation (Bernard et al, 2006), whilst the initial decrease in the expression levels of cytotoxic T-cell marker CD8a in the anterior kidney, which is the major haematopoietic tissue in trout, could be due to the migration of these activated immune cells to other sites of IHNV infection.…”