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Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20852
In the present study, we show that human self-MHC-reactive
(autoreactive) T cell clones are functionally distinct from Ag-specific
T cell clones. Self-MHC-reactive T cells exhibited helper function for
B cell Ig production when cultured with non-T cells alone, and they
exhibit suppressor function when cultured with PWM- or rCD40 ligand
(rCD40L)-activated non-T cells, whereas tetanus toxoid (TT)-specific
clones exhibited only helper function in the presence of TT with or
without PWM or rCD40L. Addition of neutralizing Abs to the cultures
showed that the suppression was mediated by TGF-ß but not by IL-10 or
IFN-
. The self-MHC-reactive clones also inhibited proliferation of
primary CD4+ T cells and TT-specific T cell clones, but in
this case the inhibition was mediated by both IL-10 and TGF-ß. In
further studies, the interactions between self-MHC-reactive T cell
clones and non-T cells that led to suppressor cytokine production have
been explored. We found that prestimulation of non-T cells for 8 h
with PWM or for 48 h for rCD40L results in non-T cells capable of
inducing self-MHC-reactive T cell to produce high levels of TGF-ß and
IL-10. In addition, these prestimulation times coincided with peak
induction of HLA-DR and costimulatory B7 molecule (especially CD86)
expression on B cells. Finally, addition of CTLA-4/Fc or blocking
F(ab')2 anti-CTLA-4 mAb, plus optimally stimulated
non-T cells, to cultures of self-MHC-reactive clones inhibited the
induction of TGF-ß but not IL-10 or IFN- production. In summary,
these studies show that activated self-MHC-reactive T cells have the
cytokine phenotype of Th3 or T regulatory cell 1 and thus may be
important regulatory cells that mediate oral and peripheral tolerance
and prevent the development of autoimmunity.
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