BAX, a heterodimeric partner of BCL2, counters BCL2 and promotes apoptosis in gain-of-function experiments. A Bax knockout mouse was generated that proved viable but displayed lineage-specific aberrations in cell death. Thymocytes and B cells in this mouse displayed hyperplasia, and Bax-deficient ovaries contained unusual atretic follicles with excess granulosa cells. In contrast, Bax-deficient males were infertile as a result of disordered seminiferous tubules with an accumulation of atypical premeiotic germ cells, but no mature haploid sperm. Multinucleated giant cells and dysplastic cells accompanied massive cell death. Thus, the loss of Bax results in hyperplasia or hypoplasia, depending on the cellular context.
Peripheral immune tolerance is generally thought to result from cross-presentation of tissue-derived proteins by quiescent tissue-resident dendritic cells to self-reactive T cells that have escaped thymic negative selection, leading to anergy or deletion. Recently, we and others have implicated the lymph node (LN) stroma in mediating CD8 T cell peripheral tolerance. We demonstrate that LN-resident lymphatic endothelial cells express multiple peripheral tissue antigens (PTAs) independent of the autoimmune regulator (Aire). They directly present an epitope derived from one of these, the melanocyte-specific protein tyrosinase, to tyrosinase-specific CD8 T cells, leading to their deletion. We also show that other LN stromal subpopulations express distinct PTAs by mechanisms that vary in their Aire dependence. These results establish lymphatic endothelial cells, and potentially other LN-resident cells, as systemic mediators of peripheral immune tolerance.
Lymphatic endothelial cells (LECs) induce peripheral tolerance by direct presentation to CD8 T cells (T CD8) IntroductionIt has been well established that intrinsic peripheral tolerance in self-reactive T cells occurs through anergy or deletion. Early work demonstrated that anergy in vitro was because of lack of CD28 costimulation, 1 which also led to deletional tolerance in vivo. 2,3 However, in other models, CD28 costimulation was required for tolerance induction. 4,5 In addition, induction of peripheral deletion and/or anergy in vivo could be reversed by costimulation through CD27, 4-1BB, and OX40. 6,7 While these costimulatory pathways operate at distinct points in the response of T cells to foreign antigens, they all induce IL-2 production, [8][9][10][11] and are associated with up-regulation of antiapoptotic molecules and enhanced survival. 10,[12][13][14] However, the basis for their reversal of tolerance induction has not been established.Inhibitory signals through programmed cell death 1 (PD-1) and B-and T-lymphocyte attenuator (BTLA) receptors, via their ligands programmed cell death-1 ligand 1 (B7-H1; also known as PD-L1) and herpesvirus entry mediator (HVEM), also have been reported to diminish T-cell accumulation and/or acquisition of effector activity in in vitro 15 and in vivo [16][17][18][19][20] models of tolerance. Interfering with these pathways enables self-reactive T cells to accumulate in secondary lymphoid organs and become fully differentiated effectors that cause autoimmunity. [16][17][18][19] Inhibitory signals through lymphocyte activation gene-3 (LAG-3) also diminish T-cell accumulation in peripheral tissue in vivo, 21 but a role for LAG-3 in CD8 T-cell (T CD8 ) tolerance induction in secondary lymphoid organs has not been established. In response to foreign antigens, signaling via these inhibitory pathways is associated with inhibition of IL-2 production [22][23][24] and diminished expression of antiapoptotic molecules. 23 However, it has yet to be clearly established how a lack of costimulation and inhibitory signaling are related to one another during peripheral tolerance induction. Finally, the cells that express the ligands for these inhibitory receptors during peripheral tolerance induction in vivo have yet to be identified.Peripheral tolerance has classically been ascribed to dendritic cells (DCs) that cross-present self-antigen acquired from peripheral tissues. 25 More recently, it has been demonstrated that it can also be mediated via direct presentation by 3 different lymph node (LN) stromal cell (LNSC) populations, including extrathymic Aireexpressing cells, 26 fibroblastic reticular cells (FRCs), 27 and lymphatic endothelial cells (LECs). 28 We previously reported that LECs directly present an epitope derived from tyrosinase, a melanocyte differentiation protein that is recognized by T CD8 recovered from melanoma and vitiligo patients, and induce peripheral tolerance through deletion of tyrosinase-specific T CD8 . 28 Here, we determined the roles of both costimulatory and ...
Immunotherapeutic drugs that mimic sphingosine 1-phosphate (S1P) disrupt lymphocyte trafficking and cause T helper and T effector cells to be retained in secondary lymphoid tissue and away from sites of inflammation. The prototypical therapeutic agent, 2-alkyl-2-amino-1,3-propanediol (FTY720), stimulates S1P signaling pathways only after it is phosphorylated by one or more unknown kinases. We generated sphingosine kinase 2 (SPHK2) null mice to demonstrate that this kinase is responsible for FTY720 phosphorylation and thereby its subsequent actions on the immune system. Both systemic and lymphocyte-localized sources of SPHK2 contributed to FTY720 induced lymphopenia. Although FTY720 was selectively activated in vivo by SPHK2, other S1P pro-drugs can be phosphorylated to cause lymphopenia through the action of additional sphingosine kinases. Our results emphasize the importance of SPHK2 expression in both lymphocytes and other tissues for immune modulation and drug metabolism.Sphingosine 1-phosphate (S1P) 2 receptor agonists are likely to be the next generation of pharmacologic agents used to modulate immune system function. The prototype drug of this class is FTY720, which is highly efficacious in prolonging allograft survival and in ameliorating autoimmune disease in a variety of animal models (1-4). FTY720 is being tested in human trials for the indications renal transplantation and multiple sclerosis (5). Further, there is mounting evidence that S1P agonists are efficacious in animal models of atherosclerosis (6), renal ischemia-reperfusion injury (7), and acute lung injury (8).FTY720 is a sphingosine analog that, after activation by phosphorylation (to FTY720-P), disrupts lymphocyte trafficking by decreasing lymphocyte egress from lymph nodes and the thymus (9, 10). Although the precise mechanisms that underlie this phenomenon are uncertain, the profound lymphopenia that is the index of FTY720 action is dependent on agonist action at lymphocyte S1P 1 receptors. Since FTY720-P is also a potent agonist at the S1P 3 , S1P 4 , and S1P 5 receptors (11, 12), it remains unknown whether the multiple therapeutic benefits of the drug correlate with agonist activity at the S1P 1 receptor. The propensity for S1P 1 receptor responses to desensitize (13) and the similar behaviors of S1P 1 receptor null thymocytes and FTY720-treated mouse lymphocytes have led to the suggestion that FTY720-P is a functional antagonist (14). In this scenario, the drug exaggerates S1P tone to the extent that the lymphocyte S1P 1 receptor signaling is chronically down-regulated.The kinase(s) responsible for FTY720 activation is the gateway whereby S1P signaling can be accessed readily with a therapeutic agent. Knowledge of this enzyme is important specifically to guide S1P prodrug design and generally to gain insight into the normal role of S1P in immune function. The identity of the kinase is not known currently; two candidates are sphingosine kinase 1 (SPHK1) and sphingosine kinase 2 (SPHK2). These enzymes, which are expressed widely, catalyz...
This is the first comprehensive review of rodent models of both infectious and autoimmune disease of testis/epididymis, and their clinical implications, i.e. their importance in understanding male infertility related to infectious and non-infectious/autoimmune disease of the reproductive organs.
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