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Departments of
*
Medicine/Rheumatology and
Immunology, Mayo Clinic and Foundation, Rochester, MN 55905
Expansion of CD4+CD28null T cells is a
characteristic finding in patients with rheumatoid arthritis. Despite
lacking CD28 molecules, these unusual CD4 T cells undergo clonal
proliferation and form large and long-lived clonal populations. They
produce high levels of IFN-
, exhibit autoreactivity, and have
cytolytic function. The mechanisms facilitating the expansion and
longevity of CD4+CD28null T cell clones in vivo
are unknown. Here, we report that CD4+CD28null,
but not CD4+CD28+, T cells express MHC class
I-recognizing receptors normally found on NK cells.
CD4+CD28null T cells preferentially expressed
killer cell activating receptors (KAR), often in the absence of killer
cell inhibitory receptors. Cross-linking of KAR molecules enhanced the
proliferative response to TCR-mediated stimulation, but not the
cytolytic function of CD4+CD28null T cells,
suggesting different signaling pathways in CD4 T cells and NK cells.
Triggering of KAR signaling led to the phosphorylation of several
cellular targets, although the pattern of phosphorylation differed from
that induced by the TCR. Aberrant expression of KAR molecules in the
absence of inhibitory receptors and in the appropriate HLA setting may
lead to the clonal outgrowth of autoreactive
CD4+CD28null T cells commonly seen in
rheumatoid arthritis.
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