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 February 2003 Vol 3 No 3 VIEWPOINTS



 
Nature Reviews Immunology (online only); doi:10.1038/nri1043

VIEWPOINT
Regulatory CD4+CD25+ T cells are 'suppressor' T cells

Joerg Ermann and C. Garrison Fathman

Center for Clinical Immunology at Stanford, Stanford University School of Medicine, Department of Medicine, Division of Immunology & Rheumatology, CCSR Building, Room 2225, Stanford, California 94305-5166, USA. Correspondence to C.G.F. e-mail: cfathman@stanford.edu

T cells come in different and overlapping phenotypes, which challenges the ability of immunologists to classify them appropriately. What is a regulatory T cell? Why do we not call T helper (TH) cells, which orchestrate immune responses against invading pathogens, regulatory? Regardless of semantics, the term 'regulatory T cell' is currently used for T cells that 'negatively' affect immune responses. 'Suppressor T cell' would perhaps be a better description, but this term is burdened with negative historical connotations. It is time for the immunology community to come to terms with its past and revisit it, to explain the suppressor-cell phenomena described more than 30 years ago.
 

Many investigators use the term 'regulatory T cell' in an even more restricted manner, referring to a subpopulation of CD4+CD25+ T cells. However, it is unclear how closely the phenotypes of suppressor activity and expression of CD25 overlap, in particular under environmental conditions that are not specific-pathogen free. CD25 is expressed by conventional T cells after stimulation, and it has been shown that in human peripheral blood, only the CD4+CD25hi T cells are 'suppressors'. Some investigators believe that high-level expression of CD62L allows for better identification of the regulatory subpopulation among CD4+CD25+ T cells. However, our data on the adoptive transfer of CD4+CD25+ T cells in models of type 1 diabetes (see further reading by Szanya et al.) and graft-versus-host disease (J.E., unpublished observations) indicate that the differential regulatory capacities of the CD4+CD25+CD62Lhi and CD4+CD25+CD62Llow subsets in vivo reflect differences in homing properties, rather than suppressor potential per se.

In addition to CD4+CD25+ T cells, there have been descriptions of regulatory CD4+CD25 T-cell populations, and interleukin-10-producing TR1 cells and transforming growth factor-ß-secreting TH3 'regulatory' cells have also been described, which might or might not overlap with CD4+CD25+ T-cell populations. Better markers or combinations of markers, and a nomenclature that correctly reflects the complexity of regulatory T-cell populations, are clearly required.

The idea that defects in CD4+CD25+ T cells contribute to the development of autoimmune diseases in humans is intriguing, although there is limited supporting evidence so far. Most animal models of autoimmunity that are used to study CD4+CD25+ T cells require drastic measures, such as neonatal thymectomy or adoptive transfer of T cells into immunodeficient animals, for disease expression, and they are therefore highly artificial. For spontaneous autoimmune diseases, such as type-1 diabetes in non-obese diabetic (NOD) mice, there is no consensus as to whether there is a defect in CD4+CD25+ T-cell numbers or function. A recent publication by Kukreja et al. described reduced frequencies of CD4+CD25+ T cells in patients with type 1 diabetes. However, in human peripheral blood, the distinction between CD4+CD25+ and CD4+CD25 cells by flow cytometry is less clear than in mouse spleens. Any comparison between patients and healthy controls might need to be carried out in a 'blinded' manner to avoid investigator bias.

To explore rigorously the hypothesis that quantitative defects of CD4+CD25+ T cells are a risk factor for the development of human autoimmune disease, we also need more information about the factors controlling the pool size of CD4+CD25+ T cells in different compartments, as well as data on the variation of CD4+CD25+ T-cell frequencies in the normal human population. Finally, defects in CD4+CD25+ T cells might be more subtle than a detectable bulk reduction in the number of these cells in the peripheral blood, and might involve 'holes' in the T-cell receptor repertoire or polymorphisms in genes controlling functional aspects, such as receptor and cytokine expression or cell trafficking.

References and links

FURTHER READING
Szanya, V. et al. The subpopulation of CD4+CD25+ splenocytes that delays adoptive transfer of diabetes expresses L-selectin and high levels of CCR7. J. Immunol. 169, 2461–2465 (2002)|PubMed|
Kukreja, A. et al. Multiple immuno-regulatory defects in type-1 diabetes. J. Clin. Invest. 109, 131–140 (2002) |PubMed|
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