T. Namekawa et al., Killer cell activating receptors function as costimulatory molecules on CD4(+)CD28(null) T cells clonally expanded in rheumatoid arthritis, J IMMUNOL, 165(2), 2000, pp. 1138-1145
Expansion of CD4(+)CD28(null) T cells is a characteristic finding in patien
ts with rheumatoid arthritis, Despite lacking CD28 molecules, these unusual
CD4 T cells undergo clonal proliferation and form large and long-lived clo
nal populations, They produce high levels of IFN-gamma, exhibit autoreactiv
ity, and have cytolytic function. The mechanisms facilitating the expansion
and longevity of CD4(+)CD28(null) T cell clones in vivo are unknown. Here,
we report that CD4(+)CD28(null), but not CD4(+)CD28(+), T cells express MH
C class I-recognizing receptors normally found on NK cells. CD4(+)CD28(null
) 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 stimulati
on, but not the cytolytic function of CD4(+)CD28(null) 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, Aber
rant expression of KAR molecules in the absence of inhibitory receptors and
in the appropriate HLA setting may lead to the clonal outgrowth of autorea
ctive CD4(+)CD28(null) T cells commonly seen in rheumatoid arthritis.