Co-inhibitory molecules: Controlling the effectors or controlling the controllers?

Thangavelu, Govindarajan; Smolarchuk, Christa; Anderson, Colin C.

doi:10.4161/self.1.2.11548

Cited by 20 publications

(14 citation statements)

References 174 publications

(217 reference statements)

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“…Success of allograft transplantation is influenced by various factors. The current studies have shown that PD-1 plays a critical role in the spontaneous acceptance of weakly mismatched allografts and thus supports the idea that potentiation of naturally induced co-inhibitory signals (Thangavelu et al 2010), such as via PD-1 (Gao et al 2003), could be exploited as a mechanism to achieve transplantation tolerance.…”

Section: Discussionsupporting

confidence: 68%

“…The balance between co-stimulation and co-inhibition influences the outcome of immune responses by allowing strong immune response against appropriate foreign antigens and maintaining tolerance to self-antigens (Sinclair and Anderson 1996;Thangavelu et al 2010). Cytotoxic lymphocytic antigen-4 (CTLA-4; CD152), programmed death-1 (PD-1; CD279) and B and T lymphocyte attenuator (BTLA; CD272) are some of the major co-inhibitory molecules that have been shown to be involved in immunological tolerance.…”

Section: Introductionmentioning

confidence: 99%

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The role of co-inhibitory signals in spontaneous tolerance of weakly mismatched transplants

et al. 2011

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The immune system of female H-2(b) (C57BL/6) mice is a strong responder against the male minor-H antigen. However rejection or acceptance of such weakly mismatched grafts depends on the type of tissue transplanted. The mechanism responsible for such spontaneous graft acceptance, and its relationship to the natural mechanisms of tolerance of self antigens is unknown. Co-inhibitory molecules negatively regulate immune responses, and are important for self tolerance. We examined whether co-inhibitory molecules play a critical role in "spontaneous" allograft tolerance. Naïve or donor sensitized diabetic female C57BL/6 (B6) wild type (WT), PD-1(-/-), and BTLA(-/-) mice were transplanted with freshly isolated syngeneic male islet grafts. The role of co-inhibitors during priming of anti-donor responses and graft challenge was also assessed using monoclonal antibodies targeting co-inhibitory receptors. Among the co-inhibitor (CTLA-4, PD-1) specific antibodies tested, only anti-PD-1 showed some potential to prevent spontaneous acceptance of male islet grafts. All BTLA(-/-) and almost all PD-1(-/-) recipients maintained the ability to spontaneously accept male islet grafts. While spontaneous graft acceptance in naïve recipients was only weakly PD-1 dependent, tolerance induced by the accepted islets was found to be highly PD-1 dependent. Furthermore, spontaneous graft acceptance in pre-sensitized recipients showed an absolute requirement for recipient PD-1 but not BTLA. Thus, the PD-1 pathway, involved in self tolerance, plays a critical role in spontaneous tolerance induced by weakly mismatched grafts in naïve recipients and spontaneous graft acceptance in pre-sensitized recipients.

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Section: Discussionsupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

The role of co-inhibitory signals in spontaneous tolerance of weakly mismatched transplants

et al. 2011

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“…Numerous co-inhibitory pathways have been identified and while each may contribute to self-tolerance, their specific functions are almost certainly unique [41]. Identification of their unique functions should provide more refined strategies for tolerance induction in autoimmunity and transplantation.…”

Section: Discussionmentioning

confidence: 98%

Programmed death-1 is required for systemic self-tolerance in newly generated T cells during the establishment of immune homeostasis

Thangavelu

Parkman

Ewen

et al. 2011

Journal of Autoimmunity

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Lymphopenia driven T cell activation is associated with autoimmunity. That lymphopenia does not always lead to autoimmunity suggests that control mechanisms may exist. We assessed the importance of the co-inhibitory receptor programmed death-1 (PD-1) in the control of lymphopenia-driven autoimmunity in newly generated T cells vs. established peripheral T cells and in thymic selection. PD-1 was not required for negative selection in the thymus or for maintenance of self tolerance following transfer of established PD-1⁻/⁻ peripheral T cells to a lymphopenic host. In contrast, PD-1 was essential for systemic self tolerance in newly generated T cells under lymphopenic conditions, as PD-1⁻/⁻ recent thymic emigrants (RTE), generated after transfer of PD-1⁻/⁻ hematopoietic stem cell (HSC) precursors or thymocytes into lymphopenic adult Rag⁻/⁻ recipients, induced a rapidly lethal multi-organ inflammatory disease. Disease could be blocked by using lymph node deficient recipients, indicating that lymphopenia driven PD-1⁻/⁻ T cell activation required access to sufficient lymph node stroma. These data suggested that PD-1⁻/⁻ mice themselves might be substantially protected from autoimmunity because their T cell repertoire is first generated early in life, a period naturally deficient in lymph node stroma. Consistent with this idea, neonatal Rag⁻/⁻ recipients of PD-1⁻/⁻ HSC were resistant to disease. Thus, a critical role of PD-1 resides in the control of RTE in lymphopenia. The data suggest that PD-1 and a paucity of lymphoid stroma cooperate to control autoimmunity in newly generated T cells. Clinical therapies for autoimmune disease employing lymphoablation and hematopoietic stem cell transplantation will need to take into account functional polymorphisms in the PD-1 pathway, if the treatment is to ameliorate rather than exacerbate autoimmunity.

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“…Coinhibitory molecules such as CTLA-4, PD-1, and BTLA have been shown to be involved in the maintenance of self-tolerance (19,20). We considered PD-1 as a strong candidate to negatively regulate the capacity for bystander killing because of its function as a coinhibitory receptor and the wide distribution of one of its ligands, PDligand 1, which is expressed in both lymphoid and parenchymal tissues, including islets (21) 14).…”

Section: Differential Control Of Target and Bystander Injurymentioning

confidence: 99%

Control of In Vivo Collateral Damage Generated by T Cell Immunity

Thangavelu

Gill

Boon

et al. 2013

The Journal of Immunology

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An ongoing dilemma faced during an immune response is generating an effective, often proinflammatory response to eliminate pathogens and/or infected cells while also minimizing collateral damage to adjacent noninfected tissues. The factors limiting bystander cell injury during an Ag-specific immune response in vivo are largely unknown. In this study, using an in vivo model of islet transplants in TCR transgenic mice, we show that both CD4 and CD8 T cells do have the capacity to inflict adjacent tissue damage and that this injury is greatly enhanced in sensitized hosts. CD4 T cell–mediated killing of specific and bystander cells occurred via different mechanisms. Unlike specific target cell killing, CD4-mediated bystander injury required tissue Fas expression and was inhibited with anti–IFN-γ Ab treatment in vivo. Moreover, bystander cell injury was not entirely nonspecific but rather required, in naive recipients, that the MHC allele expressed by the bystanders was self. Importantly, the coinhibitor programmed death-1 plays an important role in restraining bystander cell injury mediated either by defined TCR transgenic T cells or by polyclonal T cell populations. Thus, the differential requirements for specific versus bystander cell injury suggest that there are opportunities for inhibiting immune pathology without compromising Ag-specific immunity in vivo.

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Co-inhibitory molecules: Controlling the effectors or controlling the controllers?

Cited by 20 publications

References 174 publications

The role of co-inhibitory signals in spontaneous tolerance of weakly mismatched transplants

The role of co-inhibitory signals in spontaneous tolerance of weakly mismatched transplants

Programmed death-1 is required for systemic self-tolerance in newly generated T cells during the establishment of immune homeostasis

Control of In Vivo Collateral Damage Generated by T Cell Immunity

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