Abnormal differentiation of memory T cells in systemic lupus erythematosus.
OBJECTIVE
The chemokine receptor CCR7 and the tumor necrosis factor receptor family member CD27 define 3 distinct, progressively more differentiated maturational stages of CD4 memory subpopulations in healthy individuals: the CCR7+, CD27+, the CCR7-, CD27+, and the CCR7-, CD27- populations. The goal of this study was to examine maturational disturbances in CD4 T cell differentiation in systemic lupus erythematosus (SLE), using these phenotypic markers.


METHODS
Phenotypic analysis by flow cytometry, in vitro stimulation experiments, telomere length measurement, and determination of inducible telomerase were carried out. RESULTS. In SLE patients, significant increases of CCR7-, CD27- and CCR7-, CD27+ and a reduction of CCR7+, CD27+ CD4 memory T cells were found. In vitro stimulation of SLE T cells showed a stepwise differentiation from naive to CCR7+, CD27+ to CCR7-, CD27+ to CCR7-, CD27-; telomere length and inducible telomerase decreased in these subsets in the same progressive sequence. The in vitro proliferative response of these populations progressively declined as their susceptibility to apoptosis increased. Interestingly, a significant reduction in inducible telomerase was noted in SLE naive and CCR7+, CD27+ CD4+ memory T cells. Additionally, SLE CCR7-, CD27+ and CCR7-, CD27- CD4 memory T cells proliferated poorly in response to in vitro stimulation and underwent significantly more apoptosis than their normal counterparts. Finally, expression of CXCR4 was significantly reduced in all SLE subsets compared with normal.


CONCLUSIONS
Together these data indicate an increased degree of in vivo T cell stimulation in SLE, resulting in the accumulation of terminally differentiated memory T cells with a decreased proliferative capacity and an increased tendency to undergo apoptosis upon stimulation.
Fritsch
Ruth D
RD
NIAMS, NIH, Building 10, Room 6D47C, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Shen
Xinglei
X
Illei
Gabor G
GG
Yarboro
Cheryl H
CH
Prussin
Calman
C
Hathcock
Karen S
KS
Hodes
Richard J
RJ
Lipsky
Peter E
PE
D000328:Adult; D017209:Apoptosis / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007156:Immunologic Memory; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D008297:Male; D010641:Phenotype; D054400:Receptors, CCR7; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D019098:Telomerase / Q000032:analysis / Q000502:physiology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000235:genetics / Q000378:metabolism
C515370:CCR7 protein, human; D054400:Receptors, CCR7; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D019098:Telomerase