Differential changes in CD4+ and CD8+ effector and regulatory T lymphocyte subsets in the testis of rats undergoing autoimmune orchitis

Jacobo, Patricia Verónica; Guazzone, Vanesa Anabella; Jarazo-Dietrich, S.; Theas, María Susana; Lustig, Livia

doi:10.1016/j.jri.2009.04.005

Cited by 78 publications

(84 citation statements)

References 38 publications

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“…A further insight into the importance of the relative proportions of the differing types of T lymphocyte is shown by the finding that the CD8 + effector population increased more than CD4 + Foxp3 + Tregs during EAO. This imbalance could be sufficient to overwhelm the immunosuppressive actions of CD4 + Foxp3 + Treg function and thus lead to chronic testicular inflammation (49).…”

Section: Discussionmentioning

confidence: 99%

Testosterone Replacement Effectively Inhibits the Development of Experimental Autoimmune Orchitis in Rats: Evidence for a Direct Role of Testosterone on Regulatory T Cell Expansion

Fijak

Schneider

Klug

et al. 2011

The Journal of Immunology

181

154

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Despite the immune-privileged status of the male genital tract, infection and inflammation of the male genital tract are important etiological factors in male infertility. A common observation in clinical and experimental orchitis as well as in systemic infection and inflammation are decreased levels of testosterone. Emerging data point to an immunosuppressive role of testosterone. In our study, we substituted testosterone levels in experimental autoimmune orchitis (EAO) in rat by s.c. testosterone implants. EAO development was reduced to 17% when animals were treated with low-dose testosterone implants (3 cm long, EAO+T3) and to 33% when rats were supplied with high-dose testosterone implants (24 cm, EAO+T24) compared with 80% of animals developing disease in the EAO control group. In the testis, testosterone replacement in EAO animals prevented the accumulation of macrophages and significantly reduced the number of CD4+ T cells with a strong concomitant increase in the number of regulatory T cells (CD4+CD25+Foxp3+) compared with EAO control. In vitro testosterone treatment of naive T cells led to an expansion of the regulatory T cell subset with suppressive activity and ameliorated MCP-1–stimulated chemotaxis of T lymphocytes in a Transwell assay. Moreover, expression of proinflammatory mediators such as MCP-1, TNF-α, and IL-6 in the testis and secretion of Th1 cytokines such as IFN-γ and IL-2 by mononuclear cells isolated from testicular draining lymph nodes were decreased in the EAO+T3 and EAO+T24 groups. Thus, our study shows an immunomodulatory and protective effect of testosterone substitution in the pathogenesis of EAO and suggests androgens as a new factor in the differentiation of regulatory T cells.

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Section: Discussionmentioning

confidence: 99%

Testosterone Replacement Effectively Inhibits the Development of Experimental Autoimmune Orchitis in Rats: Evidence for a Direct Role of Testosterone on Regulatory T Cell Expansion

Fijak

Schneider

Klug

et al. 2011

The Journal of Immunology

181

154

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“…50 Lymphocyte subsets shift in a rat testis undergoing autoimmune-related orchitis. 51 Mouse testes that receive pancreatic islet cell allografts destroy memory T cells and recruit Tregs. 52,53 These observations suggest that Tregs contribute to testicular immune privilege.…”

Section: Immune Privilege In the Testismentioning

confidence: 99%

Testicular defense systems: immune privilege and innate immunity

et al. 2014

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The mammalian testis possesses a special immunological environment because of its properties of remarkable immune privilege and effective local innate immunity. Testicular immune privilege protects immunogenic germ cells from systemic immune attack, and local innate immunity is important in preventing testicular microbial infections. The breakdown of local testicular immune homeostasis may lead to orchitis, an etiological factor of male infertility. The mechanisms underlying testicular immune privilege have been investigated for a long time. Increasing evidence shows that both a local immunosuppressive milieu and systemic immune tolerance are involved in maintaining testicular immune privilege status. The mechanisms underlying testicular innate immunity are emerging based on the investigation of the pattern recognition receptor-mediated innate immune response in testicular cells. This review summarizes our current understanding of testicular defense mechanisms and identifies topics that merit further investigation.

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“…Moreover, Yule & Tung (1993) showed that TNF-producing CD4C Th1 cells are the key players in disease induction. However, our previous results in rats showed that the number of CD4C and CD8C effector T (Teff) cells significantly increases in the testis in the course of EAO, suggesting involvement of both subsets in pathogenesis of this disease (Lustig et al 1993, Jacobo et al 2009). Consequently, the aim of this work is to elucidate how testis-infiltrating CD4C and CD8C Teff cell subsets contribute to autoimmune inflammatory response.…”

Section: Introductionmentioning

confidence: 96%

“…We developed an experimental model of autoimmune orchitis in rats by active immunization with testicular antigens and adjuvants (Doncel et al 1989). Testicular damage in this experimental model is characterized by an increased number of T cells, macrophages, and dendritic cells that infiltrate the interstitium and by seminiferous tubules (ST) showing apoptotic germ cells and different degrees of cell sloughing that results in aspermatogenesis and atrophy , Rival et al 2006, Jacobo et al 2009). …”

Section: Introductionmentioning

confidence: 99%

CD4+ and CD8+ T cells producing Th1 and Th17 cytokines are involved in the pathogenesis of autoimmune orchitis

Jacobo¹,

Pérez²,

Theas³

et al. 2011

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Experimental autoimmune orchitis (EAO) is a useful model to study chronic testicular inflammation and infertility. EAO is characterized by severe damage of seminiferous tubules with germ cells that undergo apoptosis and sloughing. We previously reported an increase in CD4C and CD8C effector T cells in the testes of rats with EAO. Since cytokine patterns determine T cell effector functions, in the present work we analyzed the cytokines expressed by these cells during disease development. By flow cytometry, we detected an increase in the number of tumor necrosis factor-a (TNF) and interferon -g (IFNG)-producing CD4C T cells in the testis at EAO onset. As the severity of the disease progressed, these cells declined while CD8C T cells producing TNF and IFNG increased, with the predominance of IFNG expression. As a novel finding, we identified by immunofluorescence CD4C interleukin 17 (IL17)C and CD8C IL17C cells in the testes of EAO rats, with CD4C and CD8C T cells predominating at the onset and in the chronic phase of EAO respectively. Moreover, IL17 (western blot) and IL23 content (ELISA) increased in EAO, with maximum levels in the chronic phase. These results suggest the involvement of CD4C T helper (Th) 1 and Th17 subsets as co-effector cells governing EAO onset, as well as the central contribution of CD8C T cells producing Th1 and Th17 cytokines in the maintenance of chronic inflammation. The expression of T-bet and RORgt (western blot) in the testis over the course of disease also supports the presence of Th1 and Th17 cells in the testes of EAO rats.

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Differential changes in CD4+ and CD8+ effector and regulatory T lymphocyte subsets in the testis of rats undergoing autoimmune orchitis

Cited by 78 publications

References 38 publications

Testosterone Replacement Effectively Inhibits the Development of Experimental Autoimmune Orchitis in Rats: Evidence for a Direct Role of Testosterone on Regulatory T Cell Expansion

Testosterone Replacement Effectively Inhibits the Development of Experimental Autoimmune Orchitis in Rats: Evidence for a Direct Role of Testosterone on Regulatory T Cell Expansion

Testicular defense systems: immune privilege and innate immunity

CD4+ and CD8+ T cells producing Th1 and Th17 cytokines are involved in the pathogenesis of autoimmune orchitis

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