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The Journal of Immunology, 1999, 162: 4910-4913.
Copyright © 1999 by The American Association of Immunologists

Inflammation Alone Evokes the Response of a TCR-Invariant Mouse {gamma}{delta} T Cell Subset1

Akiko Mukasa2,*, Willi K. Born*,{dagger} and Rebecca L. O’Brien3,*,{dagger}

* National Jewish Medical and Research Center, Denver, CO 80206; and {dagger} Department of Immunology, University of Colorado Health Sciences Center, Denver, CO 80262


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Whether {gamma}{delta} T lymphocytes respond to microbial Ags or to inducible host Ags remains a matter of controversy. Using several different disease models and mouse strains, we and others have seen that V{gamma}6/V{delta}1 {gamma}{delta} T cells preferentially increase among the {gamma}{delta} T cells infiltrating inflamed tissues. However, it was not clear whether bacteria are necessary to bring about this response. Therefore, we have reexamined this question using a disease model in which inflammation is induced by a purely autoimmune process involving no bacteria, bacterial products, or other foreign material: testicular cell-induced autoimmune orchitis. Using this model we found that {gamma}{delta} T cells were still plentiful among the infiltrating T lymphocytes, being 9- to 10-fold more prevalent than in spleen, and that V{gamma}6/V{delta}1+ cells again represented the predominant {gamma}{delta} T cell type. This finding shows that the response of the V{gamma}6/V{delta}1+ subset does not, in fact, depend upon the presence of bacteria or bacterial products. The stimulus triggering the response of the V{gamma}6/V{delta}1 {gamma}{delta} T cells appears to be neither foreign nor organ-specific in origin, but instead consists of a self-derived host Ag or signal induced during the inflammatory process.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Though central to our understanding of the role of {gamma}{delta} T lymphocytes in immunobiology, the type of Ags these cells recognize remains unclear. {gamma}{delta} T cell clones with specificities for nonclassical MHC class I molecules have been identified (1, 2, 3, 4), although most T cells of this type lack the accessory molecules CD4 and CD8, known to be important to the TCR-{alpha}ß in the recognition of classical class I or II MHC. In addition, some experimental evidence indicates that {gamma}{delta} T cells recognize inducible host molecules instead or as well (4, 5, 6, 7, 8). However, other studies have documented responses to microbes or microbial products, including mycobacteria (9, 10, 11) and herpesvirus (12). Previously, we reported that in mice in which orchitis has been induced by injection of Listeria into one testis, {gamma}{delta} T cells comprise a substantial fraction (~20%) of the infiltrating T lymphocytes (13). In this model, autoimmune orchitis later develops in the other testis as well, because the Listeria infection allows testis-specific autoaggressive {alpha}ß T cells to multiply and invade this ordinarily immune-privileged site. In additional experiments, we found that in both the Listeria-infected and autoimmune testis most of the infiltrating {gamma}{delta} T cells express the invariant V{gamma}6/V{delta}1 TCR (14), which normally predominates among resident {gamma}{delta} T cells in mucosal sites, such as the female reproductive tract (15, 16), the tongue (15), and the lung (17) [note that nomenclature used here for the mouse {gamma} genes is as proposed by Tonegawa and colleagues (18)]. Thus, in this model, the same type of {gamma}{delta} T cell is elicited in two differently mediated kinds of inflammation, bacteria-induced and autoimmune, provoked within a single mouse. Therefore, it appeared probable that the V{gamma}6/V{delta}1+ cells in orchitic testes were responding to an Ag that is conserved between the host and the bacteria, or to an inflammation-dependent, host-derived stimulus.

However, using this model, we could not exclude the possibility that the response of the V{gamma}6/V{delta}1+ cells was instead entirely driven by a Listeria Ag, such that activated {gamma}{delta} T cells arising from the Listeria-induced inflammation were only secondarily recruited to the other testis during autoimmune attack. Although V{gamma}6/V{delta}1+ {gamma}{delta} T cell responses have now been noted in inflammation induced in a number of systems (14, 19, 20, 21, 22, 23), in all cases, bacteria or bacterial products were part of the treatment used to provoke the inflammation. Hence, in this study, we examined responding {gamma}{delta} T cells in a different model of inflammation (24), testicular cell (TC)4 induced autoimmune orchitis, in which bacteria or adjuvants containing bacterial products such as CFA are not needed. We analyzed the {gamma}{delta} T cell repertoire in the bulk population of T cells infiltrating the testis by staining lymphocytes derived from fresh tissue, and at the clonal level by analyzing hybridomas. Again, our findings indicate that most of the responding {gamma}{delta} T cells bear the invariant V{gamma}6/V{delta}1 TCR.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Preparation of lymphocytes

Male C3H/HeN mice between the ages of 8–10 wk were used for these experiments. Mice were s.c. injected with 1 x 107 syngeneic TC three times at 2-wk intervals, as previously described (24). Briefly, the TC injected were prepared as follows: testes from normal male C3H/HeN mice, 8–10 wk of age, were teased apart with scissors in a cold sterile saline solution (HBSS) in a tissue culture dish and passed through a stainless steel mesh screen. After letting the large debris settle for several minutes, the cell suspension was transferred to a test tube and pelleted at 400 x g for 10 min, then washed two additional times in cold HBSS. After counting, TC were adjusted to a concentration of 108/ml in cold HBSS and injected. Approximately 40 days after the first injection, testis-infiltrating lymphocytes were prepared from these mice as described in our previous study (14).

Hybridoma preparation

A total of 20–30 mice were injected with TC (a large number of mice is necessary because in this model of autoimmune orchitis, the inflammation is weaker than that produced following Listeria infection). On day 40, the mice were killed, and testes were harvested. Intratesticular-infiltrating lymphocytes were cultured on anti-TCR {gamma}{delta}-coated dishes in culture medium. On the second day of culture, 10 U/ml of human rIL-2 (R&D Systems, Minneapolis, MN) was added. After 5–7 days of culture, the cells were collected for fusion with BW{alpha}-ß- (25). The fusion products were plated in 96-well dishes, and the resulting hybridomas were selected with hypoxanthine-aminopterin-thymidine (HAT) medium, as previously described (14). The {gamma}{delta} T cell hybridomas derived from two such fusions are denoted the 147 series and 148 series.

PCR and sequencing

Rearranged TCR gene sequences expressed by the hybridomas were determined by sequencing cDNA specifically amplified by PCR, as previously described (14).

Flow cytometry

Monoclonal Abs recognizing TCR-{gamma}{delta} (GL-3) (26), CD3 (KT3) (27), V{delta}6.3 (C504–17C) (28), V{gamma}4 (UC3) (29), V{gamma}5 (F536) (30), and V{gamma}1 (2.11) (31) were conjugated with FITC or biotin and used to stain testicular lymphocytes. Cells were prepared as previously described (14), except that cells from 10 to 20 mice were pooled for the analysis of the testis lymphocytes. An EPICS XL flow cytometer (Coulter, Miami, FL) was used to generate these data.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
Testicular-infiltrating {gamma}{delta} lymphocytes

Fig. 1Go shows an analysis of freshly isolated testicular lymphocytes from orchitic testes, 40 days after TC inoculation. The {gamma}{delta} T cell populations present were compared with those present in spleen [note that it is not possible to compare the infiltrating {gamma}{delta} T cells with those normally found in this site, because the testis in the nondiseased state is an immune-privileged site virtually devoid of lymphocytes (32)]. Since mAbs specific for V{gamma}6 and V{delta}1 are not available, we stained lymphocytes with mAbs specific for the V{gamma}1, V{gamma}4, and V{delta}4 subsets that are common among {gamma}{delta} T cells in the spleen and blood of mice. In normal C3H/HeN spleen, V{gamma}1+ and V{gamma}4+ {gamma}{delta} T cells comprise >70% of all {gamma}{delta} T cells (Fig. 1Go). In contrast, as we found previously using a different orchitis model, in the TC-induced autoimmune testis, V{gamma}1+ and V{gamma}4+ cells together make up only ~30% of the total {gamma}{delta} T cell population. This indicates that {gamma}{delta} T cells that infiltrate and/or expand in fresh orchitic tissue largely represent a subset or subsets less common in lymphoid tissue. Interestingly, {gamma}{delta} T cells in the spleens of these orchitic mice also showed some differences, as compared with naive C3H/HeN mice, in that the V{delta}4 cells were decreased to one-half and V{gamma}1 and V{gamma}4 to two-thirds of their normal values. We had previously noted similar changes in spleens of Listeria-induced orchitic mice, so this result indicates that the autoimmune response, rather than the Listeria infection as we had previously thought, can cause a change in the spleen {gamma}{delta} T cell repertoire.



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  		FIGURE 1. {gamma}{delta} T cells infiltrating the testes of mice with experimental autoimmune orchitis induced by TC injection largely represent subsets uncommon in lymphoid tissues. Flow cytometry was conducted as described in Materials and Methods. A, Percentages are relative to CD3+ cells. B, Percentages are relative to TCR-{gamma}{delta}+ cells. This analysis was conducted twice, pooling the lymphocytes obtained from the testes of 10 mice in the first experiment, and from 20 in the second. Profiles from the second analysis are shown, although both experiments gave similar results (specifically, in the first experiment, we detected 15.4% TCR-{gamma}{delta}+ cells among the CD3+ testes-infiltrating lymphocytes, of which 8.0% expressed V{delta}4, as opposed to 20% and 8%, respectively, in the second experiment. Reagents specific for V{gamma}1 and V{gamma}4 were not included in the first analysis).

 
The mouse contains a total of only seven V{gamma} genes (33), one of which is a pseudogene in most strains (34). Thus, only four potential V{gamma} genes could be expressed by the non-V{gamma}1+/non-V{gamma}4+ population that comprises nearly 70% of the {gamma}{delta} T cells infiltrating TC-induced orchitic testes: V{gamma}2, V{gamma}5, V{gamma}6, and V{gamma}7. However, {gamma}{delta} T cells expressing a functional V{gamma}2 gene appear to be very rare (34), whereas, in adult mice, those expressing V{gamma}5 have thus far only been reported in the skin (35), and those expressing V{gamma}7 are generally in the intestinal epithelium (36). Therefore, as in Listeria-induced orchitis (14), we suspected that many of the testis-infiltrating {gamma}{delta} T cells cells would express V{gamma}6 in their TCRs.

{gamma}{delta} T cell hybridomas from experimental autoimmune orchitis testes

We went on to examine the TCRs expressed by three {gamma}{delta} T cell hybridomas derived from infiltrating T cells in the orchitic testes. Although all three of these expressed a {gamma}{delta} TCR on their surface, none of them expressed V{gamma}1, V{gamma}4, V{delta}4, or V{gamma}5 by FACS analysis (data not shown), or by RT-PCR. However, all three {gamma}{delta} T cell hybridomas derived from TC-induced autoimmune orchitic testes expressed canonical (15) in-frame transcripts encoding a V{gamma}6/V{delta}1 TCR (Fig. 2Go). Two other {gamma}{delta} T cell hybridomas from these fusions were also obtained and found to express both V{gamma}6 and V{delta}1 transcripts, but these cells were unstable and did not persist long enough for us to complete sequence analysis of their TCR gene transcripts. Hybridoma 148 KAT5, but neither of the others, was found to have an additional secondary V{delta}1 transcript, indicating that it does not represent the same clone as 148 KAT6 which arose in the same fusion. Because hybridoma 147 KAT1 was derived from a separate fusion, all three hybridomas are therefore uniquely derived clones. In our previous work, we have found that the frequency of each {gamma}{delta} T cell type in a particular tissue is roughly equivalent to its frequency in hybridoma collections made from the same tissue. For example, the frequency of V{delta}6+ cells among {gamma}{delta} T cell hybridomas derived from normal liver (22%) agreed well with their frequency as assessed by FACS analysis (~30%) (37). Moreover, an increase in the frequency of V{gamma}6+ hybridomas in liver following Listeria infection mirrored an increase in V{gamma}6 mRNA levels detected by PCR analysis in infected vs normal liver tissue (21). Thus, V{gamma}6/V{delta}1+ {gamma}{delta} T cells do not appear to have an unusual tendency to fuse, as compared with other {gamma}{delta} T cell subsets. Therefore, we conclude that the predominant TCR expressed by {gamma}{delta} T cells infiltrating the testis in TC-induced autoimmune orchitis is the invariant V{gamma}6/V{delta}1 TCR, since only this type {gamma}{delta} T cell hybridoma was found.



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  		FIGURE 2. TCR-{gamma} and {delta} gene transcripts present in {gamma}{delta} T cell hybridomas derived from testes of mice with TC-induced autoimmune orchitis.

 
Responses of V{gamma}6/V{delta}1+ {gamma}{delta} T cells during inflammation have been noted in several systems. Previously, we reported that V{gamma}6/V{delta}1+ cells are selectively increased in liver after Listeria infection in C57BL/10 mice (21). In addition, in Listeria-induced orchitis, we found that V{gamma}6/V{delta}1+ cells increased in testes of C3H/HeN mice (14). Moreover, Olive et al. (22) have reported that V{gamma}6+ T cells are increased in the initial stages of experimental allergic encephalomyelitis in PL/JxSJ/L F1 mice. Our finding here that V{gamma}6/V{delta}1 T cells are elevated as well in the testes of mice with orchitis induced in a purely autoimmune fashion, in which, as opposed to the previous studies, no bacteria or bacterial products are used, conclusively shows that the response of the V{gamma}6/V{delta}1+ {gamma}{delta} T cells does not depend upon bacterial Ag or foreign material of any kind, or upon the host response to an infectious agent. Only autologous TC, suspended in sterile saline, were used to elicit an autoimmune response in the study presented here; no adjuvants were used, nor was any material likely to contain endotoxin (such as FCS) included in preparation of the injected TC. This indicates that inflammation alone, without the concomitant present of microbes or microbial products, is sufficient to elicit the response of these {gamma}{delta} T cells. The inflammation-provoked signal, moreover, is not likely to be organ-specific, because of the above-noted preferential response of the V{gamma}6/V{delta}1+ {gamma}{delta} T cells in liver inflammation (21).

TCR-invariant V{gamma}6/V{delta}1+ cells are also the major type of resident {gamma}{delta} T cell population present in the uterine and vaginal epithelium (15). In a prior study, we found that this subset increases greatly in number in the pregnant uterus (16). Thus, it may be that similar events in pregnancy and inflammation trigger a response of these cells.

We have shown previously that depleting mice of {gamma}{delta} T cells during Listeria-induced autoimmune orchitis exacerbates the resulting inflammation (13). Similarly, we and others have found that in other systems, for example systemic listeriosis (38, 39) and Mycobacterium tuberculosis infection (40), mice lacking {gamma}{delta} T cells show increased inflammatory damage. These findings indicate that {gamma}{delta} T cells influence the inflammatory response, and based on the findings presented here, we propose that the host inflammatory response also elicits the response of at least some types of {gamma}{delta} T cells. Whether the response of the V{gamma}6/V{delta}1+ {gamma}{delta} T cells during inflammation is triggered by the induction of a normally silent host Ag, such as a heat shock protein, which then binds to this TCR or, instead, can be elicited by inflammatory signals alone, such as cytokines, in the absence of any ligand actually binding to the TCR, has yet to be determined. A better understanding of this process could be important in developing new ways to control inflammatory damage in many human diseases.


   Acknowledgments
 
We thank Michaelann Vollmer and Elizabeth Pflum for technical assistance, and Michael Lahn, Bill Townend, and Shirley Sobus for advice on FACS analysis.


   Footnotes
 
1 This work was supported by Grant IM-748 from the American Cancer Society (to R.L.O), and by National Institutes of Health Grant RO1-AI27903 (to W.B.). In addition, salary support was provided by a postdoctoral fellowship award from the Arthritis Foundation (for A.M.), and by Research Career Development Award KO4-AI0129 from the National Institutes of Health (for R.L.O.). Back

2 Current address: Brigham and Women’s Hospital, Center for Neurologic Diseases, Boston, MA 02115. Back

3 Address correspondence and reprint requests to Dr. Rebecca O’Brien, National Jewish Medical and Research Center, Department of Medicine, 1400 Jackson Street, Denver, Colorado 80206. E-mail address: Back

4 Abbreviation used in this paper: TC, testicular cells. Back

Received for publication November 9, 1998. Accepted for publication January 28, 1999.


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 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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