Abstract
It is now accepted that red blood cells (RBCs) from healthy individuals regulate T-cell activity through modulating cytokine interactions, and that stored RBCs or RBCs from inflammatory cohorts are dysfunctional. Our study aimed to investigate how changes in RBCs that have been intentionally modified can affect T-cell activity as a mechanistic test of this modification. Exposure to a cancer cell line in culture was used to alter the cytokine profile of intact RBCs and the effect of these modified RBCs (ccRBCs) on T-cells was evaluated using flow cytometry. We used RBCs from healthy volunteers and quantified cytokines in RBC lysates and conditioned media using Luminex technology. During in vitro cancer cell exposure, RBCs sequestered a variety of cytokines including IL-8, bFGF, and VEGF. Although unmodified RBCs (oRBCs) stimulated proliferation of T-cells (Jurkat cells and peripheral blood mononucleated cells), ccRBCs augmented this proliferative response (3.5-fold and 1.9-fold more respectively). Unlike oRBCs, T-cells stimulated with ccRBCs were no longer protected from phytohemagglutinin-P-driven overexpression of GATA-3 and T-bet and these T-cells were induced to secrete a variety of cytokines including IL-17 and MCP-3. This study supports the hypothesis that RBCs are capable of binding and releasing cytokines in blood, and that modification of these cells can then also affect the T-cell response.
Highlights
It is accepted that red blood cells (RBCs) from healthy individuals regulate T-cell activity through modulating cytokine interactions, and that stored RBCs or RBCs from inflammatory cohorts are dysfunctional
The significant changes between the oRBCs and the contact modified RBCs (ccRBCs) were observed for chemokines (IL-8, MCP-1 and GRO-α), growth factors, pro-inflammatory cytokines (IL-18), and an anti-inflammatory cytokine (IL-13) (Fig. 1)
The largest observed increase was for bFGF, where, ccRBCs contained 983 ± 414 pg/mL compared with 22 ± 18 pg/mL in oRBCs
Summary
It is accepted that red blood cells (RBCs) from healthy individuals regulate T-cell activity through modulating cytokine interactions, and that stored RBCs or RBCs from inflammatory cohorts are dysfunctional. RBCs have been demonstrated to stimulate the T-cell release of inflammatory cytokines including TNF-α and IFN-γ in a dose dependent manner[5] In recent years, this activity has been shown to be dysregulated in inflammatory conditions. NSCLC cells typically secrete pro-angiogenic molecules and a variety of cytokines to promote their growth, plasma levels of a number of these signalling molecules can be correlated back to tumour progression and patient outcome[14]. This cytokine release can induce downstream effects on other cells. Investigation into this may provide some valuable insight into the use of RBCs as a diagnostic tool, and some clue into understanding the immunological processes of NSCLC biology
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