The Role of Helper T Cell Subsets in Autoimmune Diseases
Section snippets
In, Mosmann et al. [1]reported that CD4+T cell clones could be classified, based upon the cytokines they secrete, into two groups which they named Th1 and Th2. This and subsequent studies established that Th1 cells secrete IL-2, IFN-γ and LT-α (also called TNF-β), while Th2 cells secrete IL-4, IL-5, IL-6. Both Th1 and Th2 cells produce TNF-α and GM-CSF, however Th1 cells produce higher amounts of both. Conversely, IL-10 and IL-13 are produced by both Th1 and Th2 cells types; however the
Generation of th1 and th2 cell types
Naive CD4+ T cells are neither of Th1 nor Th2 type. When first stimulated with antigen and antigen presenting cells, CD4+ cells secrete low amounts of various cytokines, including IL-2, IL-4 and IFN-γ. This state has been called Th0. Polarization occurs within the first 48 h [7]; however, the Th1 or Th2 cytokine secretion patterns becomes evident only upon further re-stimulation.
Pioneering work in several laboratories, particularly those of William Paul, Susan Swain and Kenneth Murphy, has
The helper phenotype of disease-causing cells
There is consensus among investigators that Th1 cells cause EAE, diabetes, and rheumatoid arthritis. Careful analysis of the data should, however, raise some concerns.
Can th2 cells cure th1-mediated autoimmune diseases?
The question of whether or not Th2 cells can prevent or cure Th1-induced diseases has generated much interest. The topic has been addressed either directly by the transfer of Th2 cells, or indirectly by in vivo alteration of the Th1\Th2 balance.
Th3
A third type of T cell, called Th3, has been obtained following oral immunization with MBP or ovalbumin (OVA) [71]. Th3 cells secrete large amounts of TGF-β1 but low amounts of IL-4, IL-10 and IFN-γ. Contrary to the variable effects seen with IL-10, TGF-β has been invariably associated with decreased immune responses and improvement of autoimmune conditions 91, 92, 93, 94, 95, 96, 97, 98. TGF-β is secreted in a latent form and can be activated by a variety of treatments, such as proteolysis,
Conclusions
I have discussed seemingly contradictory data regarding the role of T helper cell subsets in autoimmune diseases. In particular, the Th2 subset has been found to be protective or pathogenic depending on the experimental conditions. In immunocompetent recipients, conditions which favor Th2 development prevent disease induction. This effect is likely to be mediated, to a large extent, by IL-4 which impairs the priming of naive T cells towards a Th1 pathway. However, since symptoms of autoimmune
Acknowledgements
I am grateful to Dr Werner Haas and Dr G. Jeanette Thorbecke for numerous suggestions during the preparation of the manuscript, Tanya Henderson for the preparation of the figure, and Richard Stout for the preparation of the manuscript. JJL is supported by the NIH, National Multiple Sclerosis Society, the Hirschl-Caulier Trust and the Bernard B. Levine Investigatorship in Allergy and Immunology.
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Skirball Institute for Biomedical Research and Dept. of Pathology, New York University School of Medicine, 10016 New York, NY, U.S.A. E-mail: [email protected]