 |
Gary
Litman, Ph.D. E-mail:
litmang@allkids.org |
Training
Undergraduate, University of Minnesota, Minneapolis
Ph.D., University of Minnesota, Minneapolis
Research
Interests
Studies in our laboratory are directed at determining the basis for recognition mediated by novel immune receptors. Our present efforts are focused on several nonmammalian model systems. We have identified and resolved the entire gene cluster of a large multigene family of leukocyte regulatory receptors termed novel immune-type receptors (NITRs) that likely function as innate immune receptors in zebrafish. NITRs exhibit a general overall similarity to killer cell immunoglobulin-like receptors (KIRs), a form of natural killer cell receptor in man, but encode variable (V) region ectodomains, which are as diversified as those encoded by the germline forms of V regions of immunoglobulin and T cell antigen receptors (TCRs) but do not undergo somatic reorganization. We have identified both inhibitory and activating forms of NITRs and have demonstrated binding of soluble chimeric NITRs to allogenic target cells. We presently are examining cell lineage-specific expression and ligand binding of NITRs by exploiting the efficient transgenesis and translucent character of the developing zebrafish embryo.
Parallel studies in the skate, a cartilaginous fish, representing an even earlier divergence in the vertebrate radiations, have uncovered an even more extensive family of leukocyte regulatory receptors termed the modular domain immune-type receptors (MDIRs). Although the MDIRs do not encode V regions, they exhibit overall greater structural complexity than the NITRs; both activating and inhibitory forms have been identified. No clear orthologs of MIDRs are apparent in other jawed vertebrate lineages. Ongoing efforts are directed at identifying MDIR ligands and characterizing their cell lineage-specific expression.
Our third model system is amphioxus, a protochordate. We have identified a novel family of diversified genes that encode VCBPs (variable region chitin-binding domain proteins). These apparently bifunctional molecules exhibit regionalized germline hyperdiversity in their N-terminal V regions and demonstrate enormous interindividual variation. In surveys of large numbers of animals, we do not find any two individuals that possess the same VCBP repertoire. We have solved a crystal structure for the V region-encoding portion of a VCBP and can relate genetic diversity to structural features of the molecule. Current studies are focused on understanding the basis for the genetic diversity of VCBPs, including further exploring the possibility that they undergo somatic change(s), as well as determining their ligand binding specificity and overall function.
The increasing experimental accessibility of non-mammalian jawed vertebrates, jawless vertebrates, protochordates and invertebrates is providing new information regarding the likely patterns of emergence of immune-related molecules during metazoan phylogeny, as well as the evolution of alternative mechanisms for receptor diversification. Findings such as those described above blur traditional distinctions between adaptive and innate immunity and emphasize that, through evolution, the immune system has used a remarkably extensive variety of solutions to meet fundamentally similar requirement for host protection.
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search will be conducted at the US National Library of Medicine (NLM) and PubMed.
Selected
Publications
Hernandez Prada JA, Haire RN, Allaire M, Jakoncic J, Stojanoff V, Cannon JP, Litman GW, Ostrov DA. Ancient evolutionary origin of diversified variable regions revealed by crystal structures of an amphioxus VCBP. Nat Immunol 2006; 7:875-882.
Litman GW, Cannon JP, Dishaw LJ. Reconstructing immune phylogeny: new perspectives. Nat Rev Immunol 205; 5:866-879.
Litman GW, Cannon JP, Rast JP. New insights into alternative mechanisms of immune receptor diversification. Adv Immunol 2005; 87:209-236.
Yoder JA, Litman RT, Mueller MG, Desai S, Dobrinski KP, Montgomery JS, Buzzeo MP, Ota T, Amemiya CT, Trede NS, Wei S, Djeu JY, Humphray S, Jekosch K, Hernandez Prada JA, Ostrov DA, Litman GW. Resolution of the novel immune-type receptor gene cluster in zebrafish. Proc Natl Acad Sci USA 2004; 101:15706-15711.
Cannon JP, Haire RN, Schnitker N, Mueller MG, Litman GW. Individual protochordates have unique immune-type receptor repertoires. Curr Biol. 2004; 14:R465-466.
Cannon JP, Haire RN, Litman GW. Identification of diversified genes that contain immunoglobulin-like variable regions in a protochordate. Nat Immunol 2002; 3:1200-1207.
Cancer Biology Ph.D. Program
H. Lee Moffitt Cancer Center, MRC-4 East
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Tampa, Florida 33612
Phone: 813-745-6876
E-mail: CancerPHD@moffitt.org
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