Abstract
Background
While oligoclonality of circulating CD4− CD8− and of CD8+ T cells is not uncommon, clonal dominance within the CD4 compartment is not frequently found in healthy individuals. In contrast, the majority of patients with rheumatoid arthritis (RA) have clonally expanded CD4+ T cell populations. Previous studies have demonstrated that these clonogenic CD4+ T cells do not express the CD28 molecule. To examine the correlation between CD28 expression and clonal proliferation, we have analyzed the T cell receptor (TCR) diversity of CD4+ CD28− T cells in normal individuals and in RA patients.
Material and Methods
The size of the peripheral blood CD4+ CD28− compartment was determined in 30 healthy individuals and 30 RA patients by two-color FACS analysis. In 10 RA patients and five controls with more than 2.5% CD4+ CD28− T cells, TCR BV gene segment usage was analyzed with 19 BV-specific antibodies. Oligoclonality was assessed in sorted CD4+ CD28+ and CD28− T cells using TCR BV-BC-specific polymerase chain reaction and size fractionation. Clonal dominance was confirmed by direct sequencing.
Results
The CD4+ CD28− T cell compartment was expanded to more than 2.5% in 70% of the RA patients and 30% of the normal individuals. Compared with the CD4+ CD28+ T cells, the TCR BV gene segment usage among CD4+ CD28− cells was grossly skewed with the dominance of single BV elements. Molecular TCR analysis provided evidence for oligoclonality in 17 of 21 expanded BV elements. In two unrelated RA patients who shared both HLA-DRB1 alleles, the TCR β-chain sequences of dominant clonotypes were highly conserved.
Conclusions
Oligoclonality is a characteristic feature of CD4+ CD28− T cells which are expanded in some healthy individuals and in the majority of RA patients. The lack of CD28 expression is a common denominator of CD4+, CD8+, and CD4− CD8− T cells prone to develop clonal dominance. The limited TCR diversity of clonal CD4+ CD28− populations in RA patients suggests that these T cells recognize a limited spectrum of antigens. The fact that the majority of individuals with marked expansions and oligoclonality of CD4+ CD28− T cells are RA patients suggests a role for these unusual lymphocytes in the pathogenetic events leading to RA.
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Acknowledgments
Supported in part by National Institutes of Health grants (ROI AR41974 and AR42527) and by the Mayo Clinic and Foundation. The authors thank Toni L. Higgins for secretarial support and James W. Fulbright for technical assistance.
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Schmidt, D., Martens, P.B., Weyand, C.M. et al. The Repertoire of CD4+ CD28− T Cells in Rheumatoid Arthritis. Mol Med 2, 608–618 (1996). https://doi.org/10.1007/BF03401644
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DOI: https://doi.org/10.1007/BF03401644