Trends in Immunology

Trends in Immunology

Volume 23, Issue 9, 1 September 2002, Pages 450-455
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Review
Pathogen-specific regulatory T cells provoke a shift in the Th1/Th2 paradigm in immunity to infectious diseases

https://doi.org/10.1016/S1471-4906(02)02288-3Get rights and content

Abstract

Current dogma suggests that immunity to infection is controlled by distinct type 1 (Th1) and type 2 (Th2) subpopulations of T cells discriminated on the basis of cytokine secretion and function. However, a further subtype of T cells, with immunosuppressive function and cytokine profiles distinct from either Th1 or Th2 T cells, termed regulatory T (Tr) cells has been described. Although considered to have a role in the maintenance of self-tolerance, recent studies suggest that Tr cells can be induced against bacterial, viral and parasite antigens in vivo and might prevent infection-induced immunopathology or prolong pathogen persistence by suppressing protective Th1 responses. These observations have significant implications for our understanding of the role of T cells in immunity to infectious diseases and for the development of new therapies for immune-mediated disorders.

Section snippets

Tr1 cells

T cells, from ovalbumin (OVA) T-cell receptor (TCR)-transgenic mice, cultured with OVA and IL-10 result in the generation of T-cell clones with a unique cytokine profile distinct from that of Th0, Th1 or Th2 cells. These Tr1 cells produce IL-10 and IL-5, with or without TGF-β, but with little or no IL-2, IL-4 or interferon (IFN)-γ production, and proliferate poorly following polyclonal TCR-mediated activation [1]. More recently, in vitro manipulation with immunosuppressive drugs and anti-IL-4

Role of Tr cells in infection

The demonstration of Th1 and Th2 subtypes of T cells in the 1980s provided a useful conceptual framework for understanding immunity to infectious diseases. It predicted that immunity to intracellular pathogens was mediated by Th1 cells, which activate macrophages and promote B cells to secrete complement-fixing and virus-neutralizing IgG2a antibodies, whereas immunity to extracellular pathogens was mediated by Th2 cells, which provide helper activity for antibody production, especially IgG1,

Differentiation of Tr cells

Tr cells, similar to Th1 and Th2 cells, arise from naı̈ve precursors and can be differentiated in vitro. Although there is little evidence for cytokine-mediated differentiation of CD4+CD25+ Tr cells, TGF-β could be involved in the generation and expansion of human CD4+ CD25+ Tr cells [44]. In the case of murine Tr1 cells, it has been shown that IL-10 might act as a differentiation factor but not as a growth factor for these cells [4]. Furthermore, recent studies have demonstrated that human CD4+

Conclusions and future perspectives

The resurgent interest in suppressor, reborn as regulatory, T cells is set to change the face of cellular immunology and will probably have a major impact on our understanding of the pathogenesis and treatment of a range of human diseases. The ability to induce memory T cells that produce suppressive cytokines on stimulation with specific antigen in vivo has opened up the possibility of developing vaccines against autoimmune diseases and therapies to control graft rejection, graft-versus-host

Definition of regulatory T (Tr) cells

Immunosuppressive T cells with cytokine profiles distinct from either type 1 (Th1) or type 2 (Th2) T cells.

Questions to be addressed

  • •

    Can functional subtypes of Tr cells be distinguished phenotypically?

  • •

    What is the lineage relationship of CD4+CD25+ cells to Tr1 and Th3 cells?

  • •

    Are there distinct types of DC responsible for the induction of different Tr cells?

  • •

    Do Tr cells have effector functions other than immunosuppression?

  • •

    Do Tr cells have a role in limiting inflammatory pathology or in pathogen persistence?

  • •

    Are Tr (rather than Th2) cells primarily responsible for controlling Th1 response in vivo, for example, in response to

Acknowledgements

This work was supported by The Science Foundation Ireland, The Wellcome Trust and The Health Research Board of Ireland. We apologize to authors that we were unable to quote due to space limitations.

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