OBJECTIVE: T cells deficient in CD28 expression have been implicated in the pathogenesis of rheumatoid arthritis (RA). Given that CD28-null T cells are functionally heterogeneous, we undertook this study to screen for novel receptors on these cells. METHODS: Seventy-two patients with RA (ages 35-84 years) and 53 healthy persons (32 young controls ages 19-34 years, 21 older controls ages 39-86 years) were recruited. Phenotypes and proliferative capacity of T cells from fresh leukocytes and of long-term cultures were monitored by flow cytometry. Lung biopsy specimens from patients with RA-associated interstitial pneumonitis (IP) were examined by immunohistochemistry. Receptor functionality was assessed by crosslinking bioassays. RESULTS: Chronic stimulation of CD28(+) T cells in vitro yielded progenies that lacked CD28 but that gained CD56. Ex vivo analysis of leukocytes from patients with extraarticular RA showed a higher frequency of CD56(+),CD28-null T cells than in patients with disease confined to the joints or in healthy controls. CD56(+),CD28-null T cells had nil capacity for proliferation, consistent with cellular senescence. CD56(+) T cells had skewed T cell receptor (TCR) alpha/beta-chain usage and restricted TCR third complementarity-determining region spectra. Histologic studies showed that CD56(+) T cells were components of cellular infiltrates in RA-associated IP. CD56 crosslinking on T cells sufficiently induced cytokine production, although CD56/TCR coligation induced higher production levels. CONCLUSION: Chronic activation of T cells induces counterregulation of CD28 and CD56 expression. The loss of CD28 is accompanied by the gain of CD56 that confers TCR-independent and TCR-dependent activation pathways. We propose that accumulation of CD56(+) T cells in RA contributes to maladaptive immune responses and that CD56(+) T cells are potential targets for therapy.
OBJECTIVE: T cells deficient in CD28 expression have been implicated in the pathogenesis of rheumatoid arthritis (RA). Given that CD28-null T cells are functionally heterogeneous, we undertook this study to screen for novel receptors on these cells. METHODS: Seventy-two patients with RA (ages 35-84 years) and 53 healthy persons (32 young controls ages 19-34 years, 21 older controls ages 39-86 years) were recruited. Phenotypes and proliferative capacity of T cells from fresh leukocytes and of long-term cultures were monitored by flow cytometry. Lung biopsy specimens from patients with RA-associated interstitial pneumonitis (IP) were examined by immunohistochemistry. Receptor functionality was assessed by crosslinking bioassays. RESULTS: Chronic stimulation of CD28(+) T cells in vitro yielded progenies that lacked CD28 but that gained CD56. Ex vivo analysis of leukocytes from patients with extraarticular RA showed a higher frequency of CD56(+),CD28-null T cells than in patients with disease confined to the joints or in healthy controls. CD56(+),CD28-null T cells had nil capacity for proliferation, consistent with cellular senescence. CD56(+) T cells had skewed T cell receptor (TCR) alpha/beta-chain usage and restricted TCR third complementarity-determining region spectra. Histologic studies showed that CD56(+) T cells were components of cellular infiltrates in RA-associated IP. CD56 crosslinking on T cells sufficiently induced cytokine production, although CD56/TCR coligation induced higher production levels. CONCLUSION: Chronic activation of T cells induces counterregulation of CD28 and CD56 expression. The loss of CD28 is accompanied by the gain of CD56 that confers TCR-independent and TCR-dependent activation pathways. We propose that accumulation of CD56(+) T cells in RA contributes to maladaptive immune responses and that CD56(+) T cells are potential targets for therapy.
Authors: Miao He; Lisa E Kratz; Joshua J Michel; Abbe N Vallejo; Laura Ferris; Richard I Kelley; Jacqueline J Hoover; Drazen Jukic; K Michael Gibson; Lynne A Wolfe; Dhanya Ramachandran; Michael E Zwick; Jerry Vockley Journal: J Clin Invest Date: 2011-03 Impact factor: 14.808
Authors: Abbe N Vallejo; Robert G Mueller; David L Hamel; Amanda Way; Jeffrey A Dvergsten; Patricia Griffin; Anne B Newman Journal: Ageing Res Rev Date: 2010-10-12 Impact factor: 10.895
Authors: Lewis H Kuller; Rachel H Mackey; Brian T Walitt; Kevin D Deane; V Michael Holers; William H Robinson; Jeremy Sokolove; Yuefang Chang; Simin Liu; Christine G Parks; Nicole C Wright; Larry W Moreland Journal: Arthritis Rheumatol Date: 2014-03 Impact factor: 10.995
Authors: Jeffrey A Dvergsten; Robert G Mueller; Patricia Griffin; Sameem Abedin; Allyson Pishko; Joshua J Michel; Margalit E Rosenkranz; Ann M Reed; Daniel A Kietz; Abbe N Vallejo Journal: Arthritis Rheum Date: 2013-08