Monocyte:T‐cell interaction regulates human T‐cell activation through a CD28/CD46 crosstalk

Abstract

T cell activation requires engagement of the T cell receptor and of at least one costimulatory molecule. The key role of CD28 in inducing T cell activation has been reported several decades ago and the molecular mechanisms involved well described. The complement regulator CD46 also acts as a costimulatory molecule for T cells but, in contrast to CD28, has the ability to drive T cell differentiation from producing some IFNγ to secreting some potent anti-inflammatory IL-10, acquiring a so-called Type I regulatory phenotype (Tr1). Proteolytic cleavage of CD46 occurs upon costimulation and is important for T cell activation and IL-10 production. The observation that CD46 cleavage was reduced when PBMC were costimulated compared to purified naive T cells led us to hypothesize that interactions between different cell types within the PBMC were able to modulate the CD46 pathway. We show that CD46 downregulation is also reduced when CD4+ T cells are co-cultured with autologous monocytes. Indeed, monocyte:T cell co-cultures impaired CD46–mediated T cell differentiation and coactivation, by reducing downregulation of surface CD46, lowering induction of the early activation marker CD69, as well as reducing the levels of IL-10 secretion. Blocking of CD86 could partly restore CD69 expression and cytokine secretion, demonstrating that the CD28-CD86 pathway regulates CD46 activation. Direct concomitant ligation of CD28 and CD46 on CD4+ T cells also modulated CD46 expression and regulated cytokine production. These data identify a crosstalk between two main costimulatory pathways and provide novel insights into the regulation of human T cell activation.

Dental follicle mesenchymal stem cells down‐regulate Th2‐mediated immune response in asthmatic patients mononuclear cells

“…43 In a study, it was stated that un-stimulated monocytes have the ability to modulate T cell activation in the culture wells, because monocytes can undergo slight differentiation after plating into culture wells. 44 A current study suggested that resting monocytes of non-atopic asthmatic patients showed low expression of CD80 and high expression of CD86 when stimulated with LPS in the culture. 45 In this study, we investigated the effect of DFSCs on the activation of costimulatory molecules on monocytes in PBMC.…”

“…The initiation of signalling mechanism begins with the presentation of antigens by MHC‐class II and activation of costimulatory molecules (CD80, CD83 and CD86), which CD86 induced with allergen‐specific responses . In a study, it was stated that un‐stimulated monocytes have the ability to modulate T cell activation in the culture wells, because monocytes can undergo slight differentiation after plating into culture wells . A current study suggested that resting monocytes of non‐atopic asthmatic patients showed low expression of CD80 and high expression of CD86 when stimulated with LPS in the culture .…”

Differential mucosal IL‐10‐induced immunoregulation of innate immune responses occurs in influenza infected infants/toddlers and adults

“…17,20 The level of IL-10 production from macrophages/ monocytes could have been influenced by the lower absolute counts of T cells in young mice 41 but follow-up studies will be needed to confirm this. Moreover, from prior studies, 42,43 there are clear links between interactions of CD4 T cells and monocytes that affect each other's activities. At present, we do not know if differences in absolute T-cell counts, loss of IL-10 co-producing T cells in the lymph nodes that feed the lungs, a failure of young dendritic cells to adequately prime for co-producing cells, or whether other local lung factors that influence IL-10 co-production are not present in young mice.…”

Quantitative analysis of cell proliferation by a dye dilution assay: Application to cell lines and cocultures

“…Studying the coculture systems of T cells and monocytes is important to identify different mechanisms in the progression and therapeutic effects of several diseases such as cancer, inflammatory diseases, arthritis, and neurodegenerative diseases (49,50). To demonstrate the simultaneous measurement of cell proliferation in a mixed coculture, we applied the dye dilution assay to mixed populations: cocultures comprising (i) suspension type cells Jurkat and THP-1, and (ii) adherent and suspension type cells, U2OS and THP-1.…”

“…Playing a role in immune defense, T cells and monocytes are rapidly recruited to eliminate infected or transformed cells at the sites of infection or inflammation, and cocultures are often used to study various factors involved in their interaction. Studying the coculture systems of T cells and monocytes is important to identify different mechanisms in the progression and therapeutic effects of several diseases such as cancer, inflammatory diseases, arthritis, and neurodegenerative diseases (49,50). Also, the crosstalk between immune cells and cancer cells is important in cancer progression and metastasis in many cancers including osteocarcinoma (51) and adenocarcinoma (52).…”