Premature Cell Senescence and T Cell Receptor–Independent Activation of CD8+ T Cells in Juvenile Idiopathic Arthritis

Abstract

Objectives CD8T cells lacking CD28 were originally reported by Wedderburn and colleagues as a characteristic feature of JIA, but the relevance of these unusual cells to JIA remains to be elucidated. Because of recent evidence that CD28 loss is typical of terminally differentiated lymphocytes, we examined for functional subsets of CD8T cells in JIA. Methods Following informed consent/assent, blood and/or waste synovial fluid were collected from children with definite diagnosis of JIA (n = 98). De-identified blood (n = 33) and cord blood (n = 13) samples from healthy donors were also collected. CD8T and CD4T cells were screened for novel receptors, and where indicated, bioassays were performed to determine functional relevance of the identified receptor. Results Patients had a naïve T cell compartment with shortened telomeres, and their entire T cell pool had reduced proliferative capacity. They had an over abundance of CD31+CD28null CD8T cells, which was a significant feature of oligoarticular JIA (n = 62) compared to polyarticular JIA (n = 36). CD31+CD28null CD8T cells had limited mitotic capacity, and expressed high levels of the senescence antigens γH2Ax and/or p16. Ligation of CD31, independent of the TCR, sufficiently induced tyrosine phosphorylation, vesicle exocytosis, and production of IFN-γ and IL-10. Conclusion These data provide the first evidence for cell senescence, represented by CD31+CD28null CD8T cells, in the pathophysiology of JIA. Activation of these unusual cells in a TCR-independent manner suggests they are maladaptive, and could be potential targets for immunotherapy.

In Vivo Imaging of Venous Side Cerebral Small-Vessel Disease in Older Adults: An MRI Method at 7T

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Relationships of pulmonary function, inflammation, and T-cell activation and senescence in an HIV-infected cohort

“…CD28 null T-cells, however, are functionally heterogeneous, due to the induction of cell surface receptors that can either have detrimental or beneficial function. For example, de novo expression of CD31 on CD28 null CD8 + T-cells and CD56 on CD28 null CD4 + T-cells is associated with the oligoarticular subtype of juvenile idiopathic arthritis[72] and with idiopathic lung disease in young adults with rheumatoid arthritis[73], respectively. In contrast, studies of successfully aging octo/nonagenarians show expression of various NK-related related receptors on CD28 null CD4 + and CD8 + T-cells, with triggering of such receptors leading to production of immune protective cytokines such as IL-2 and interferon γ[20,74].…”

Cellular senescence impact on immune cell fate and function

“…CD28 null T lymphocytes accumulate during aging and cancer presumably due to a prolonged exposure to common persistent antigens (Effros et al ., 2003; Effros, 2011). They are also found in young individuals as a result of chronic antigenic stimulation (Effros et al ., 2003; Effros, 2011) or chronic immune degenerative disorders such as juvenile idiopathic arthritis (Dvergsten et al ., 2013), myelodysplastic syndromes (Xiao et al ., 2013), idiopathic CD4 lymphopenia (Bignon et al ., 2015), or RA (Schönland et al ., 2003). The loss of CD28 is not only a result of T‐cell receptor (TCR) activation.…”