CD4+ regulatory cells as a potential immunotherapy

Abstract

CD4(+) regulatory T (T(R)) cells represent a unique lineage of thymically generated lymphocytes capable of powerfully suppressing immune responses. A large body of experimental data has now confirmed the key role played by these cells in the maintenance of self-tolerance. Increasingly, the importance of these cells is also being recognized in a host of other clinically relevant areas such as transplantation, tumour immunity, allergy and microbial immunity. Additionally, it is also possible to generate T(R) cells by using a variety of ex vivo experimental approaches. We will focus here on harnessing the suppressive abilities of both these families of regulatory cells and how this should give us access to a potent cell-based immunotherapy appropriate for clinical application.

Figure 1

Relationship of thymically and extrathymically generated regulatory cells. T cells emerge from the thymus as either regulatory cells (T_R) or conventional naive T cells (Th0). The pathological responses of autoreactive effector cells (T_E) can be suppressed by the action of both thymically (T_R) and peripherally (Tr1/Th3) generated regulatory cells. The developmental relationship between the two classes of regulatory cells still needs to be fully clarified but some evidence suggests that Th0 are able to differentiate into T_R cells in the periphery under special conditions.

Figure 2

Demonstrating T_R cell-mediated maintenance of self-tolerance. Induction of autoimmune diseases in T cell-deficient mice by transferring CD4⁺ splenocyte suspensions depleted of CD25⁺ cells to T cell-deficient mice. Co-transfer of purified CD25⁺CD4⁺ T cells prevents the induction of autoimmunity. Based on Sakaguchi et al. (1995).

Figure 3

Population of a graft with allospecific T_R cells results in highly stable tolerance and demonstrates dominant suppression by T_R cells. BALB/c nude mice recipients received MHC Class II mismatched B6 allografts in conjunction with adoptively transferred CD25⁻ and CD25⁺ cells (B6 1⁰). Approximately 70% of such grafts are retained more than 100 days. Mice with original surviving grafts received fresh grafts of identical haplotype (B6 2⁰) and third party grafts (C3H) and survival examined (a). Animals maintained a high localized tolerance to the original graft but only partially so to the secondary graft of identical haplotype, which was rejected albeit at a slower tempo than the third party graft (b) (kindly reproduced with permission from Oxford University Press).

Figure 4

Blockade of effector T cells allowing the in vivo expansion of alloreactive/self-reactive T_R cells: a putative immunotherapy for transplantation or autoimmunity. Following transplantation both harmful effector T cells (T_E) and suppressive natural regulatory cells (T_R) are recruited to the graft. In the normal physiological state, there are too few T_R cells or their function is too weak to beneficially suppress the large precursor frequency of graft destructive T_E cells (a). Administration of an immunotherapeutic agent (e.g. non-depleting anti-CD4) specifically blocks T_E cells but allows the function and, more importantly, alloreactive expansion of T_R cells (b). The large expanded population of T_R cells then renders the graft operationally tolerant (c). Essentially similar principles can be applied in the case of autoimmunity.

Figure 5

A putative therapeutic scheme using regulatory cells applied to organ transplantation. Both T_R and adaptive regulatory cells could potentially be used to establish allograft tolerance in the absence of standard immunosuppression. Intervention could be made at several stages. (a) In the case of bone marrow grafting, fresh recipient T_R cells or (b) ex vivo-expanded T_R cells could be suffused with the graft. (c) Donor-specific T_R or adaptive regulatory cells could be generated and expanded ex vivo on a source of donor antigen (e.g. PBMCs or biopsy material). (d) Recipient T_R cells could expand naturally on the graft in vivo following transplantation. Meanwhile host effector cell responses would be held in check by immunosuppressive treatment allowing expansion of T_R cells to effective levels, before drug treatment is phased-out. CIN, Calcineurin inhibitors.