Unusual T cell receptor in opossum

doi:10.1126/science.abg7639

GSTDTAP > 气候变化

DOI	10.1126/science.abg7639
	Unusual T cell receptor in opossum
	Michael F. Criscitiello
	2021-03-26
发表期刊	Science
出版年	2021
英文摘要	B and T lymphocytes of the vertebrate adaptive immune system have structurally, genetically, and evolutionarily related receptors for antigen recognition that initiate immune responses with notable specificity and memory. In general, the antigen binding sites of these receptors are evolutionarily conserved, yet a few very different immunoglobulin (Ig) structures have been characterized from shark, camelids, and cow B cells. On page 1383 of this issue, Morrissey et al. ([ 1 ][1]) reveal the structure of an opossum T cell receptor (TCR) that also eschews the vertebrate norm. This marsupial TCR is the latest in an emerging trend of smaller, projecting structural domains that are used for antigen recognition by the adaptive immune systems of some species, and it might have therapeutic potential. From sharks to man, vertebrates have two varieties of T lymphocytes for orchestration of immune responses through cytokine secretion and direct killing of infected or cancerous cells. T cells of αβ and γδ lineages differentiate in the thymus where they rearrange genetic loci encoding either an αβ or a γδ heterodimeric TCR for antigen recognition. More than a decade ago, a fifth TCR chain in the older nonplacental mammals (including platypus, echidna, and marsupials), called TCRµ, was discovered ([ 2 ][2]). Although most similar to TCRδ, TCRµ is encoded at a distinct locus and was predicted to have two variable domains at its membrane-distal amino terminus. Little is known of the T cells that express TCRµ. ![Figure][3] Reaching for antigen TCRγµ is part of a growing trend of T and B cell antigen receptors with reach. Most vertebrate antigen receptors bind antigen with six CDRs, three contributed by V domains of each partner chain (heavy and light chains, TCRα and β, or TCRγ and δ). TCRµ is the latest to break from this canon. GRAPHIC: C. BICKEL/ SCIENCE Morrissey et al. greatly extend our understanding of TCRµ and the cells that express it. Although the TCRµ chain was found not to be expressed in the peripheral blood mononuclear cells in opossums, nearly as many γµ T cells were found in the spleen as αβ-expressing T cells. In addition to confirming TCRγ as the heterodimeric partner of the TCRµ chain, single-cell RNA sequencing analysis showed that most of the γµ T cells use the CD8αα+ homodimer, although some expressed neither the CD4 nor the CD8 TCR coreceptor. The more common CD8αβ+ heterodimer is used by cytotoxic T lymphocytes. CD8αα+ function is largely unknown, although in humans it can be an inhibitory coreceptor on natural killer cells ([ 3 ][4]). Functional studies will have to determine if TCRγµ signaling is inhibitory or more regulatory in nature. The usual structure of the TCR is similar to one antigen binding arm (Fab) of Ig (including secreted antibodies) produced by B cells. The TCR and Fab of Ig are a heterodimer of two chains, each comprising a constant domain and a variable domain, which is diversified by somatic gene rearrangement. Three hypervariable loops from each variable domain interact with antigen differently in each lymphocyte, providing a repertoire of antigen recognition for the host's immune defense. The three hypervariable loops of each variable domain are called complementarity-determining regions (CDRs). CDR1 and CDR2 are encoded within a variable (V) gene segment; CDR3 is the product of the DNA junctions produced by the rearrangement of V, diversity (D), and joining (J) gene segments in lymphocyte development. Notably, the TCRγ variable gene rearrangements that paired with marsupial TCRµ showed restricted diversity compared with those pairing with TCRδ, often relying on microhomology in the ends of Vγ2 and Jγ3. This supports the idea that TCRγ variable domains may play a supportive role for the TCRµ chain rather than contribute to antigen recognition. CDR3 of the protruding membrane-distal TCRµ domain was longer and more diversified, which is suggestive of a role in antigen recognition. The TCRγµ crystal structures reported by Morrissey et al. show a projecting µ variable domain with a relatively long and diverse CDR3, which is more similar to Ig variable domains in amino acid sequence and structure than to the variable domains of TCRs. Because the TCRγ chain does not provide a variable domain partner for the TCRµ membrane-distal variable domain, the authors rightly compare TCRµ to the Igs that do not use light chains: camelid single-domain antibodies (VHH) ([ 4 ][5]) and immunoglobulin new antigen receptor (IgNAR) from cartilaginous fish ([ 5 ][6]). These Igs have a lone variable domain jutting out without three adjacent CDRs provided by an Ig light chain (see the figure). The structures ([ 6 ][7]) of these single–variable domain paratopes (antigen binding sites) are being developed as immunotherapeutics, including for COVID-19 ([ 7 ][8]). These single-domain binders nearly have the specificity of traditional monoclonal antibodies but are less bulky so they can access sites and bind recessed epitopes. This may also be the case for marsupial TCRµ. Another lymphocyte antigen receptor that appears to break the two–variable domain and six-CDR paradigm occurs in sharks. NARTCR comprises two variable domains and a TCRδ constant domain ([ 8 ][9]), possibly to yield a structure convergent upon that of marsupial TCRµ ([ 9 ][10]). Additionally, a textbook-defying antigen receptor was discovered in cattle, which contains a subset of ultralong Ig heavy chain CDR3 “cattlebodies” ([ 10 ][11]). Hyperactivation of AID (activation-induced cytidine deaminase) for somatic hypermutation diversifies CDR3 ([ 11 ][12]), which has produced broadly neutralizing cattlebodies to HIV when cows were immunized with gp120 ([ 12 ][13]). The study of Morrissey et al. is a reminder of how conserved B and T cell antigen receptor immunogenetics are and how the interrelationships of antibodies and TCR are not only obvious in ancestral shark immunity but also in mammals. The antigen binding variable domain of the TCRµ paratope is similar to various single-domain Ig structures that have evolved in other species; whether they bind antigen similarly remains unknown. This perpetuates an emerging theme of Ig heavy chain variable domains being used on TCRδ in most vertebrate taxa, along with somatic hypermutation of TCR loci, demonstrating general plasticity between Ig and TCR immunogenetic components and diversification mechanisms ([ 13 ][14]). It is doubtful that these instances are as phylogenetically rare as they seem now. “Reaching,” smaller, protruding paratopes will continue to be engineered into human antibodies, and perhaps one day the TCR as well. Studies of thymic development of γµ T cells, identification of the antigens or ligands bound, and assays of cellular effector function will be needed to understand if this third TCR heterodimer also defines a third lineage of T cells. However, it is now clear that many taxa of diverse vertebrates have innovated the lymphocyte antigen receptor away from the relatively planar, six-CDR paratope to somatically diversify a smaller, more probing antigen binding surface. Human malaria patients can also make similar single-domain antibody paratopes ([ 14 ][15]). Perhaps these TCRs with reach will also be suited for immunotherapeutics. 1. [↵][16]1. K. A. Morrissey et al ., Science 371, 1383 (2021). [OpenUrl][17][Abstract/FREE Full Text][18] 2. [↵][19]1. Z. E. Parra et al ., Proc. 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领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/321082
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Michael F. Criscitiello. Unusual T cell receptor in opossum[J]. Science,2021.
APA	Michael F. Criscitiello.(2021).Unusual T cell receptor in opossum.Science.
MLA	Michael F. Criscitiello."Unusual T cell receptor in opossum".Science (2021).