Activating NK‐cell receptors co‐stimulate CD4⁺CD28⁻ T cells in patients with rheumatoid arthritis

Abstract

Effector T‐cell responses can be modulated by competing positive or negative signals transduced by NK‐cell receptors (NKR). In the CD4+ T‐cell population, the expression of NKR is primarily found in the CD4+CD28− T‐cell subset, also known as CD28null T cells. These T cells are frequently found in rheumatoid arthritis (RA) and other inflammatory disorders, suggesting that signaling through NKR may play a role in the autoimmune reaction. Here we aimed to dissect the phenotype and function of NKR‐expressing CD4+CD28− T cells in patients with RA. By analyzing a broad array of NKR on CD4+CD28− T cells we found a significant expression of the co‐activating receptors 2B4 (CD244), DNAM‐1 (CD226), and CRACC. Pair‐wise ligations of 2B4 with DNAM‐1 and/or NKG2D lead to increased effector functions of primary CD4+CD28− T cells to suboptimal levels of anti‐CD3 stimulation. Using multi‐parameter flow cytometry, we demonstrate that such co‐ligation led to an increased magnitude in overall responsiveness without changing qualitative aspects of the response. Altogether these results demonstrate a pattern of additive effects in NKR‐mediated functional modulation of CD4+CD28− T cells in RA. This may have consequences for the inflammatory responses imposed by these cells, thus influencing disease manifestations.

High Numbers of Differentiated Effector CD4 T Cells Are Found in Patients with Cancer and Correlate with Clinical Response after Neoadjuvant Therapy of Breast Cancer

“…S2E). Altogether, this phenotype is compatible with the expansion of chronically antigen-stimulated highly differentiated effector CD4s in untreated mUMs, similar to what has been described in other settings such as chronic viral infection (21,27,29) or rheumatoid arthritis (32)(33)(34), with however, three distinctive features when compared with the similar subset found in healthy donors: an effector phenotype associated with a cytotoxic potential instead of a memory phenotype, few cycling cells, and no IL-10 secretion.…”

“…were observed in other chronic antigen stimulations, without complete characterization of their phenotype or effector functions (30)(31)(32)(33)(34)(35). The chCD4s present in patients with cancer are probably related to these previously described subsets.…”

“…Indeed, these features have been observed in diseases in which chronic antigen stimulation is obvious, such as HIV infection (27,29,30), or hypothesized, such as rheumatoid arthritis and multiple sclerosis (31)(32)(33)(34)(35). In mUMs, CD28 expression was low on effector chCD4s (Fig.…”

DNA demethylation and histone H3K9 acetylation determine the active transcription of the NKG2D gene in human CD8+T and NK cells

“…The overexpression of NKG2DL in healthy cells can disrupt the balance between immune activation and tolerance, and promote autoimmune responses favoring the development of rheumatoid arthritis (RA), multiple sclerosis and celiac disease. 4,41,42 The pathogenesis of RA is characterized by excessive production of IL-15 and TNF-α in the sera, and inflamed synovial joints, which induce the expression of an unusual subset of NKG2D-expressing CD4 + T cells. Moreover, NKG2DL MICA and MICB are highly upregulated in synovial tissue of RA patients, activating the T cells in an NKG2D-dependent manner.…”

“…alba Fernández-sánchez, 1 aroa Baragaño Raneros, 1 Reyes carvajal palao, 1 ana B. sanz, 2 alberto Ortiz, 3,4 Francisco Ortega, 4,5 Beatriz suárez-Álvarez 1, † and carlos López-Larrea…”