The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/2/583/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 4, February 17, 1997 583-600

Articles

Induction of Apoptosis and T Helper 2 (Th2) Responses Correlates with Peptide Affinity for the Major Histocompatibility Complex in Self-reactive T Cell Receptor Transgenic Mice

C.I. Pearson*, W. van Ewijk{ddagger}, and H.O. McDevitt*

From the * Department of Microbiology and Immunology, Stanford University Medical Center, Stanford, California 94305; and {ddagger} Department of Immunology, Erasmus Universiteit Rotterdam, Postbus 1738, 3000 DR Rotterdam, The Netherlands

Multiple sclerosis is an autoimmune disease thought to be mediated by CD4+ T helper cells (Th). Experimental autoimmune encephalomyelitis is a rodent model of multiple sclerosis and has been used extensively to explore a variety of immunotherapies using soluble protein or peptide antigens. The underlying mechanisms of such therapy have been attributed to induction of T cell anergy, a switch in Th1 to Th2 responses, or peripheral deletion of autoreactive T cells. In this study, we have developed transgenic mice expressing a T cell receptor (TCR) specific for the NH2-terminal peptide Ac1-11 of the autoantigen myelin basic protein to explore the mechanism of soluble peptide therapy. T cells from these mice are highly skewed toward the CD4 population and have an abnormal thymic architecture, a phenomenon found in other TCR transgenic mice that exhibit a highly skewed CD4/CD8 ratio. Soluble Ac1-11 or the analogues Ac1-11[4A] or Ac1-11[4Y] (which bind to the major histocompatibility complex [MHC] class II molecule I-Au with increasing affinities) given intravenously activates T cells, rendering cells hyperresponsive in vitro for at least two days after injection. Concomitantly, T cells apoptose in the periphery, the degree of which correlates with the affinity of the peptide for the MHC. In addition, a shift in the T helper phenotype of the surviving T cells occurs such that the low affinity peptide, Ac1-11, induces primarily a Th1 response, whereas the highest affinity peptide, Ac1-11[4Y], induces primarily a Th2 type response. These data show that both the nature and the presumed number of the peptide–MHC complexes formed during specific peptide therapy affect both the degree of peripheral programmed cell death as well as the outcome of the T helper subset response in vivo, leading to amelioration of disease.

Address correspondence to Dr. Hugh O. McDevitt, Department of Microbiology and Immunology, Fairchild Bldg. D345, Stanford University Medical Center, Stanford, CA 94305.

1 Abbreviations used in this paper: AICD, activation-induced cell death; APL, altered peptide ligands; DP, double positive; EAE, experimental autoimmune encephalomyelitis; FasL, Fas ligand; HA, hemagglutinin; LT, lymphotoxin; MBP, myelin basic protein; mTNF, membrane-bound TNF-{alpha}; SP, single positive; TNFR, TNF receptor.


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