Summary The autoimmune regulator (AIRE) is essential for prevention of autoimmunity; its role is best understood in the thymus where it promotes self-tolerance through tissue-specific antigen (TSA) expression. Recently, extrathymic Aire-expressing cells (eTACs) have been described in murine secondary lymphoid organs, but the identity of such cells and their role in immune tolerance remains unclear. Here we have shown that eTACs are a discrete major histocompatibility complex class II (MHC II)hi, CD80lo, CD86lo, epithelial cell adhesion molecule (EpCAM)hi, CD45lo bone marrow-derived peripheral antigen presenting cell (APC) population. We also have demonstrated that eTACs can functionally inactivate CD4+ T cells through a mechanism that does not require regulatory T cells (Treg), and is resistant to innate inflammatory stimuli. Together these findings further define eTACs as a distinct tolerogenic cell population in secondary lymphoid organs.
In the past 20 years, our understanding of the workings of complement regulatory protein, CD46 (membrane cofactor protein), has grown as has the impressive list of pathogens interacting with this membrane-bound complement inhibitor. Referred to as a "pathogen magnet," CD46 serves as a receptor for seven human pathogens. Initially discovered as a widely expressed C3b- and C4b-binding protein, it was subsequently shown to be a cofactor for the serine protease factor I to inactivate by limited proteolysis these two opsonins and components of the convertases. The involvement of CD46 in reproductive processes continues to be an emerging story. It is a protector of placental tissue, but it may also play a more direct role in reproduction through its expression on the inner acrosomal membrane of spermatozoa. Cross-linking CD46 with antibodies or natural or pathogenic ligands induces rapid turnover and signaling events. In this regard, much attention is currently focused on generating human T lymphocyte regulatory cells by cross-linking CD46. Finally, highlighting its importance in protecting cells against excessive complement activation is the discovery that even a heterozygous deficiency of CD46 predisposes to hemolytic uremic syndrome.
IntroductionA paramount feature of the immune system is to be able to counter an infectious threat while remaining unresponsive to antigens of healthy tissues and harmless substances. Concerning the latter, a number of mechanisms are in place to ensure such immunologic tolerance. Much interest has been focused on CD4 ϩ T-regulatory T cells (Tregs), which can modulate the activation and function of T helper type 1 (Th1) and Th2 effector cells. [1][2][3] Tregs are currently divided into 2 groups: natural (or thymic) CD4 ϩ CD25 ϩ Tregs and adaptive, peripherally induced Tr1 and Th3 cells. 2,4 Natural Tregs constitute about 10% of peripheral-blood CD4 ϩ T lymphocytes, express the transcription factor Foxp3 as well as high levels of the IL-2R alpha chain (CD25), and require exogenous IL-2. 5,6 These cells originate in the thymus, are specific for self-antigens, and act via a contact-dependent mechanism. 2,4 Adaptive Tr1 and Th3 cells are generated in the periphery against both self-and foreign antigens. 3 They also require exogenous IL-2 and mediate their suppressive effect by the secretion of immunosuppressive cytokines. 7-9 Adaptive Tregs may 5 or may not 10 express Foxp3 and show variable expression of CD25. 3 While Th3 cells secrete TGF- and seem to be central for the induction of oral tolerance, 8,11 Tr1 cells are characterized by high-level synthesis of IL-10 without concurrent IL-4 production 7,12 and may play a role in the maintenance of tolerance against enteric bacteria. 7,13-15 The interrelationships among Treg subpopulations are poorly understood and recent work suggests the existence of additional adaptive human Treg-cell types. 16 We recently discovered that CD46, a widely expressed complement inhibitor, functions as a costimulator in the activation of human peripheral CD4 ϩ T cells. Cross-linking of CD46 with either its natural ligands, such as C3b dimers 17 or the CD46-binding streptococcal M protein, 18 or with mAbs 17 in the presence of T-cell receptor (TCR) stimulation leads to the development of highly proliferative cells with a regulatory phenotype resembling Tr1 cells. 17,18 CD3/CD46-induced Tregs synthesize large amounts of IL-10 and low or undetectable quantities of IL-2, IL-4, and IL-5. They are able to suppress the activation of bystander T cells in an IL-10-dependent, contact-independent manner. 17 Their induction requires exogenous IL-2 17 but no pre-existing basal expression of Foxp3. 19 Of interest, in vitro-generated CD46-induced Tr1-like cells also demonstrate strong granzyme B and perforin expression and display contact-dependent cytotoxicity toward autologous immunocompetent T cells, including activated CD4 ϩ and CD8 ϩ T cells. 19,20 Thus, Tr1-like cells generated through CD46 activation possess 2 distinct mechanisms for T-cell suppression: secretion of IL-10 and granzyme B-mediated contact-dependent inhibition.The effect of Tregs on T-lymphocyte activation and function has received much attention, while modulation of other humanimmunocompetent T-cell populations has been less studi...
Regulatory T cells (Tregs) participate in the control of the immune response. In the human system, an IL-10-secreting, T regulatory type 1 cell (Tr1)-like subset of Tregs can be induced by concurrent cross-linking of the TCR and CD46 on naive CD4+ T cells. Because many viral and bacterial pathogens, including the major human pathogen Streptococcus pyogenes, bind to CD46, we asked whether this bacterium can directly induce Tr1-like cells through the streptococcal ligand for CD46, the M protein. The M5 and M22 proteins were found to induce T cells to develop into the IL-10-producing Tr1-like phenotype. Moreover, whole M5-expressing bacteria, but not isogenic M-negative bacteria, led to proliferation and IL-10 secretion by T cells. The interaction between the M5 protein and T cells was dependent on CD46 and the conserved C repeat region of M5. Supernatants derived from T cells stimulated with M proteins or M protein-expressing bacteria suppressed bystander T cell proliferation through IL-10 secretion. In addition, activation of CD46 through streptococcal M protein induced the expression of granzyme B, providing a second means for these cells to regulate an immune response. These findings suggest that binding to CD46 and exploiting its signaling pathway may represent a strategy employed by a number of important human pathogens to induce directly an immunosuppressive/regulatory phenotype in T cells.
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