Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation

Abstract

Treatment with ex vivo-generated regulatory T cells (T-reg) has been regarded as a potentially attractive therapeutic approach for autoimmune diseases. However, the dynamics and function of T-reg in autoimmunity are not well understood. Thus, we developed Foxp3gfp knock-in (Foxp3gfp.KI) mice and myelin oligodendrocyte glycoprotein (MOG) /IAb (MHC class II) tetramers to track autoantigen-specific effector T cells (T-eff) and T-reg in vivo during experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. MOG tetramer-reactive, Foxp3 + T-reg expanded in the peripheral lymphoid compartment and readily accumulated in the central nervous system (CNS), but did not prevent the onset of disease. Foxp3 + T cells isolated from the CNS were effective in suppressing naive MOG-specific T cells, but failed to control CNS-derived encephalitogenic T-eff that secreted interleukin (IL)-6 and tumor necrosis factor (TNF). Our data suggest that in order for CD4 + Foxp3 + T-reg to effectively control autoimmune reactions in the target organ, it may also be necessary to control tissue inflammation.Thymus-derived (natural) T-reg are crucial for preventing generalized multiorgan autoimmunity throughout the lifespan of an individual 1,2 . The importance of antigenspecific T-reg in conferring genetic resistance to organ-specific autoimmunity 3 COMPETING INTERESTS STATEMENTThe authors declare no competing financial interests.Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions NIH Public Access 10,11 .In vitro, natural T-reg are anergic and suppress T-eff responses in a cell contact-dependent manner 12 . In vivo, T-reg can proliferate and their mechanism of suppression remains largely unknown 13,14 . It was suggested that the encounter with autoantigens was required for their maintenance in vivo 15 . However, it is unclear whether expansion of antigen-specific T-reg can actually be triggered during an inflammatory autoimmune response. This is a fundamental question as T-reg that bear transgenic autoreactive T-cell receptors (TcRs) seem to suppress autoimmune diabetes better than a polyclonal T-reg population does 16 . Furthermore, it has been shown that naive T cells develop reciprocally into T-reg or pathogenic T-helper type 17 (T H 17) cells depending on the absence or presence of IL-6 in the local cytokine milieu [17][18][19] . Thus, the origin and population dynamics of T-reg in autoimmune tissue inflammation are unclear. It has been proposed that in EAE, T-reg may not even reach the target organ but may prevent the trafficking of autopathogenic T-eff into the CNS (ref. The transcription factor Foxp3 has been identified as crucial for the commitment of thymocytes to the T-reg lineage [21][22][23] . We and others have generated Foxp3gfp.KI mice in order to reliably monitor T-reg in vivo based on the linked expression of green fluorescent protein (GFP) in Foxp3 + T cells 19,24 . Using Foxp3gfp.KI mice in combination with a MOG 35-55 /IAb-specifi...

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

“…FOXP3 expression is known to be increased upon activation of human T cells [56][57][58]. However, the increased numbers of CD4 1 FOXP3 1 T cells found in autoimmune inflammatory environments such as EAE or the rheumatoid joint [59][60][61] has been used to support the argument that Treg are expanded in inflammation but are unable to establish control [62]. Although defective CTLA-4 function and an expanded CD4 1 FOXP3 1 population in lupus patients may not be connected, there is a striking parallel found in CTLA-4-deficient mice [1,2].…”

CCR6 regulates EAE pathogenesis by controlling regulatory CD4+ T‐cell recruitment to target tissues

“…Th1 and Th17 cytokine profile effector cells and antigen-specific Treg have a critical role in EAE pathogenesis [4][5][6][7][8][9][10]. In MOG-induced EAE, both antigen-specific T-effector and Treg differentiate and proliferate in the periphery before migrating to the CNS [9]. Differentiation is accompanied by sequential expression of selectins, integrins, and chemokine receptors responsible for T-cell-subset recruitment to and extravasation at inflammation sites.…”

“…Naive T cells develop reciprocally into Treg or pathogenic Th17 cells, depending on the presence or absence of IL-6 in the local cytokine milieu [17][18][19]. The inflammatory environment not only controls T-cell differentiation but also affects Treg suppressor function in the target tissue [9].CCR6 is a common marker of certain tissue-homing Treg [15,16] and Th17 cells [20]; these two cell types show a clear functional dichotomy in inflammatory processes, and both are directly involved in autoimmune disease regulation [18,19]. EAE is thus an excellent model for analysis of the CD4/Th1/Th17/ Treg pathway, and CCR6 À/À mice are useful for determining the function of this receptor in in vivo EAE development.…”

“…Naive T cells develop reciprocally into Treg or pathogenic Th17 cells, depending on the presence or absence of IL-6 in the local cytokine milieu [17][18][19]. The inflammatory environment not only controls T-cell differentiation but also affects Treg suppressor function in the target tissue [9].…”

Regulatory T cells and immune computation

“…Indeed, T cells expressing Th1, Th2 or Th17 phenotypes can inhibit the development or the activity of T reg [22,23]. Moreover, T reg are themselves indirectly regulated by the effector cells they regulate.…”