Abstract
Men and sharks are both jawed vertebrates at the top of the food chain. Sharks are the first extant to develop adaptive immunity preserved to man throughout jawed vertebrates. We hypothesize here, that T cell receptor/major histocompatibility complex (TCR/MHC) interactions developed as the defense mechanism of carnivors against takeover by their victims’ cells derived pathogens. Germline encoded TCR segments have been conserved in evolution, providing the MHC bias of TCR. Ancestor genes of MHC polymorphisms may have first developed as a mating preference system, that later in evolution provided host immune responses destroying infectious non-self, yet maintaining tolerance to self. Pathogens may thus have simultaneously selected for alloimmunity. Allorejection has been observed in sharks and men. Cannibalism is a common ecological interaction in the animal kingdom, especially prevalent in aquatic communities; it favors selection of intraspecies allo responses for defense of self integrity. Alloreactive T cells do not undergo negative selection of strong TCR/MHC interactions; thus, they react stronger than self-MHC recognizing T cells. High levels of genetic diversity at MHC genes play a critical role in protecting populations of vertebrate species from contagious cells displaying stemness and homing features, including cancer cells. Recognition of self-MHC fails especially in diseases, which predominantly arise with age and after the peak of reproduction, e.g., cancer. So far, the treatment of malignant disease with autologous T cells has widely failed. Allorecognition constitutes an extremely powerful mechanism in evolution, which may be employed in immunotherapy of cancer by MHC-disparate, e.g., haploidentical transplantation and consecutive treatment with T cells from the donor parents recognizing tumor selective peptides presented by the non-inherited haplotype on the tumor.
Highlights
Laboratory of Transplantation Biology, Children’s Cancer Research Center and Department of Pediatrics, Kinderklinik München Schwabing, Technische Universität München, München, Germany
That T cell receptor/major histocompatibility complex (TCR/MHC) interactions developed as the defense mechanism of carnivors against takeover by their victims’ cells derived pathogens
Allorecognition constitutes an extremely powerful mechanism in evolution, which may be employed in immunotherapy of cancer by MHC-disparate, e.g., haploidentical transplantation and consecutive treatment withT cells from the donor parents recognizing tumor selective peptides presented by the non-inherited haplotype on the tumor
Summary
From sharks to men recombinase activating genes RAG1 and RAG2 into an already existing non-rearranging V-like exon of an Ig-domain-containing gene that was regulating cell mediated cytotoxicity or phagocytosis (Kaufman, 2002; Van Den Berg et al, 2004). Kurosawa and Hashimoto (1997) argues that MHC variability came in before TCR variability, i.e., first, there was only one TCR These assumptions are based on the postulate, that allorecognition is MHC dominant. The recent discovery, that a single amino acid in the TCR CDR2 is conserved from shark to man and is critical for MHC recognition by TCR (Scott-Browne et al, 2011) would argue in favor of MHC recognition before peptide recognition. Since agnathan shark prey such as lamprey and hagfish did not display MHC, selective pressure for allorecognition to defend individual genetic integrity occurred first, when sharks started eating sharks: cannibalism became a constitutive feature of this extant, but not restricted to it. MHC polymorphisms may have first developed as a mating preference system, that later in evolution provided host immune responses destroying infectious non-self, yet maintaining tolerance to self
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