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The Role of Short Homology Repeats and Tdt in Generation of the Invariant Y6 Antigen Receptor Repertoire in the Fetal Thymus

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The Role of Short Homology Repeats and Tdt in Generation of the Invariant Y6 Antigen Receptor Repertoire in the Fetal Thymus View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Immunity, Vol. 3, 439-447, October, 1995, Copyright 0 1995 by Cell Press The Role of Short Homology Repeats and TdT in Generation of the Invariant y6 Antigen Receptor Repertoire in the Fetal Thymus Yi Zhang,’ Dragana Cado,’ David M. Asarnow,t In the epithelia of the skin and reproductive tract of mice Toshihisa Komori,* Frederick W. Alt,S there are unique populations of y6 T cells with very re- David H. Raulet,’ and James P. Allison’ stricted TCR repertoire (Asarnow et al., 1988, 1989; Ito- ‘Department of Molecular and Cellular Biology hara et al., 1990; Nandi and Allison, 1991). In the skin, and Cancer Research Laboratory essentially all the T cells express y chains encoded by University of California, Berkeley Vy3-Jyl segments, while those of the reproductive tract Berkeley, California 94720 are encoded by Vy4-Jyl segments. In both cases, the tBerlex, Incorporated junctions are characterized by minimal diversity, and the 15049 San Pablo Avenue absence of nongermline-encoded nucleotides. In these Richmond, California 94804 tissues there is a single and identical predominant 6 chain *Howard Hughes Medical Institute encoded by the VSl-DSP-JS2 segments. In all mouse Children’s Hospital strains examined to date, greater than 90% of the produc- Department of Genetics tively rearranged y and 6 genes in these tissues have the Harvard University Medical School same canonical junctions. These observations raise im- Boston, Massachusetts 02115 portant questions concerning the function and origin of these essentially monomorphic TCR. It has been sug- gested that these epithelial T cells perform a unique form Summary of immunological surveillance for damage-induced self- antigens (Allison and Havran, 1991; Raulet et al., 1991). Fetal thymic and adult epithelial Vy3 + and Vy4 + T cells The concept of trauma signal surveillance has gained sup- express yS antigen receptors (TCR) with invariant junc- port with the demonstration that skin-derived Vy3+ T cells tions lacking N nucleotides. Using transgenic recombi- can recognize heat-stressed keratinocytes (Havran et al., nation substrates, we show that di- or trinucleotide 1991). repeats, either in the coding region or in P elements, The precursors of epithelial Vy3’ and Vy4+ T cells are have strong effects on the site of recombination. In produced in a series of overlapping waves during fetal other mice bearing a terminal deoxynucleotidyl trans- thymic development (Havran and Allison, 1988; Allison ferase (TdT) transgene under the control of the CD2 and Havran, 1991). Moreover, Vy3’ cells are produced promoter, we found that the frequency of canonical only during fetal development in a process that require junctions was markedly reduced with a concomitant both fetal stem cells and fetal thymic microenvironment increase in in-frame noncanonical junctions with N nu- (Havran and Allison, 1990; lkutaet al., 1990). The potential cleotides. Together, our results show that short ho- TCR repertoires of these fetal precursors is constrained mology repeats direct the site of rearrangement and by the restricted expression and ordered rearrangement thus play a critical role in the generation of y6 T cell of V genes during development (Goldman et al., 1993), receptor canonical junctions. Increased TdT activity as well as by the absence of the diversifying effect of the in Vy3+ T cells has a inhibitory effect on junctional addition of random nucleotides at the junction by terminal homogeneity in these cells. deoxynucleotidyl transferase (TdT) (Landau et al., 1987; Rothenberg and Triglia, 1983). Despite these constraints, there still exists a considerable potential for diversification Introduction either by recombination at different sites or by exonucleo- lytic processing of the coding ends. Diversity in immunoglobulins and T cell antigen receptors It has been suggested that the canonical repertoire is (TCR) is generated through V(D)J rearrangement. The use generated by the effects of cellular selection (Itohara and of different germline gene segments, the imprecise joining Tonegawa, 1990). However, two recent reports suggested of gene segments, the addition of nongermline-encoded that cellular selection may not be required for the formation nucleotides, and the combinatorial association of the pro- of the invariant yS repertoires in Vy3+ and Vy4+ T cells. tein products of the rearranged genes allows potential di- Using a rearrangement-competent transgene with a versity that has been estimated as approaching 10” for frameshift mutation in the Vy3 segment upstream of the immunoglobulins, 10’” for ap TCR, and 10” for $5 TCR joints, it was demonstrated that the transgenic Vy3-Jyl (Davis and Bjorkman, 1988). For ab T cells, it is clear that canonical junctions are still formed even though the the functional repertoire in an individual is shaped by a transgene can not generate functional Vy3 protein (Asar- complex processof negative and positive selection to elim- now et al., 1993). Similarly, it was found that the Vy31Jyl inate self-reactive clones and ensure the survival of clones and VyWJyl canonical junctionswere generated in normal with the capacity to recognize peptide antigens in the con- frequencyinTCR6genemutantmice(Itoharaetal., 1993). text of self-major histocompatibility antigens (Robey and These results give support to the previous suggestion that Fowlkes, 1994). The nature of the forces that shape the the invariant repertoire is a result of directed rearrange- yS TCR repertoire is much less clear, particularly for those ment, rather than cellular selection (Raulet et al., 1991; which reside in the epithelial tissues. Allison and Havran, 1991). However, the exact mecha- Immunity 440 nisms involved in the generation of these canonical junc- repeats are sufficient to direct the V-r3/Jyl rearrangement tions remain to be determined. and formation of the Vy3/Jyl canonical junctions. The in- Previous results have shown a correlation between the fluence of TdT enzyme activity on the formation of the presence of short homology repeats near the ends of the Vy3 invariant repertoire was assessed by generating mice coding segments and the appearance of predominant carrying a transgene that expresses TdT under the CD2 junctional sequences in immunoglobulin H (IgH) gene re- promoter. The junction diversity and the frequency of N arrangement (Gu et al., 1990a, 199Ob). Short homology nucleotide addition in Vy3Nyl junctions were significantly repeats were suggested to be responsible for the limited increased in TdT transgenic mice. These data provide di- junctional diversity of neonatal immunoglobulin gene re- rect evidence that short repeats can direct the site of re- arrangement (Feeney, 1991 a, 1992). It has been proposed combination in Vy3Nyl rearrangement, and that TdT ex- that these direct repeats may help to align the broken pression can disrupt the process. Thus, the canonical Vy3 ends during the recombination process (Alt and Baltimore, junctions appear to be the result of rearrangement di- 1982; Roth and Wilson, 1986; Lieber, 1992). ATlATA short rected by short repeats in the absence of TdT. repeats are observed at the Vy3-Jyl , Vy4-Jyl , and V61- DS2 junctions in TCR y and 6 chain rearrangement (Allison Results and Havran, 1991; Raulet et al., 1991). Similarly, AGIGAGI GGA short repeats generated by P element addition ap- Role of AT Short Repeats in Directing pear to be present at the D62-J62 and D62-J61 junctions the Vy3 Rearrangement (Itohara et al., 1993). Since the junctional diversity at all To determine the function of ATshort repeat near the ends these joints is severely restricted, it seemed possible that of the Vy3lJyl coding segments in generating the y6 ca- short homology repeats might promote the formation of nonical sequences, we used a rearrangement substrate certain types of joints and thus contribute to the generation that contains the Vy4, Vy3-Jyl-Cyl coding segments in of canonical junctions. However, there has been no direct the germline configuration (Figure 1A). Termination co- evidence linking the presence of short homology repeats dons have been introduced into the Vy4 and Vy3 coding and the formation of yS canonical junctions. segments to prevent the production of Vy4 and Vy3 protein The level of TdT activity during early fetal thymic devel- products. Previous results showed that the Vy3/Jyl ca- opment may also influence the generation of canonical nonical junctions were generated at the same frequency junctions. TdT is thought to be the major enzyme activity in the transgenic substrate rearrangement as in the endog- responsible for N region addition (Alt and Baltimore, 1982). enous Vy3 gene rearrangement (Asarnow et al., 1993). Mutations in murine TdT gene resulted in total loss of N Point mutations were introduced near the 3’ end of Vy3 nucleotides in the V-D-J recombination junctions of both coding segment in the recombination substrate to destroy I3 and T lymphocytes (Komori et al., 1993; Gilfillan et al., specifically the AT direct repeat or to generate new direct 1993). Loss of TdT enzymatic activity is also considered repeats (Figure 16). Recombination substrates carrying to be responsible for the higher frequency of in-frame ca- the various mutations were injected into fertilized eggs to nonical and out-of-frame predominant Vy3-Jyl junctions generate transgenic mice. Day 17 transgenic fetal thymic in the thymus of adult mice (Komori et al., 1993; Gilfillan DNA was polymerase chain reaction (PCR) amplified us- et al., 1993). A low level of TdT enzyme activity in fetal ing primers designed to amplify specifically either trans- and neonatal spleen and liver B cells has also been sug- genie or endogenous V-J rearrangement junctions. gested to be responsible for the lack of N region diversity in immunoglobulin recombination junctions (Opstelten et al., 1986; Meek, 1990; Feeney, 1990, 1991b, 1993). It was recently shown that presence of TdT activity could dimin- A Ikb ish the effect of homology-directed rearrangement in an - in vitro recombination system (Gerstein and Lieber, 1993).
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