Abstract
Elevated levels of the cytokine TL1A is associated with several autoimmune diseases e.g. rheumatoid arthritis and inflammatory bowel disease. However, the exact role of TL1A remains elusive. In this study, we investigated the function of TL1A in a pro-inflammatory setting. We show that TL1A together with IL-12, IL-15 and IL-18 increases expression of the co-stimulatory molecules CD154 (CD40 ligand) and CD134 (OX40) on previously activated CD4+ T cells. This indicates that TL1A functions as a co-stimulatory molecule, decreasing the activation threshold of T-cells. We have previously shown that TL1A co-stimulation strongly induces IL-6 in human healthy leukocytes. Interestingly, the cytokine-activated effector T-cells did not produce IL-6 in response to TL1A, indicating distinct effects of TL1A on different cell populations. We further show that this co-stimulation increases the expression of CD25 (IL-2Rα) and CD11a (α-chain of LFA-1) on CD4 T-cells, likely governing increased IL-2/IL-15 sensitivity and cell-cell contact. Along with this, TL1A co-stimulation caused a specific induction of IL-22 and GM-CSF from the activated T-cells. These results substantially contribute to the explanation of TL1A's role in inflammation. Our results suggest that TL1A should be considered as a target for immunotherapeutic treatment of rheumatoid arthritis and inflammatory bowel disease.
Highlights
Cytokine activation or bystander activation has been observed for years, but the mechanisms skewing the regulatory/inflammatory balance have received increased attention during the last decade
We have recently shown that TL1A together with IL-12, IL-15 and IL-18 induces IL-6 and TNF-a production in leukocytes purified from healthy donors [12]
We show that TL1A induces and sustains expression of CD25, CD134, CD154 and LFA-1 on effector CD4+ T-cells
Summary
Cytokine activation or bystander activation has been observed for years, but the mechanisms skewing the regulatory/inflammatory balance have received increased attention during the last decade. The initial activation of antigen presenting cells causes the production of IL-12, IL-15 and IL-18, cytokines that are often elevated in autoimmunity [4]. These cytokines synergize in inducing IFN-c production from NK, NKT and T cells, and IL15 drives growth of NK- and memory CD8-cells [3,5]. TL1A is a pro-inflammatory cytokine that is found elevated in several diseases such as Rheumatoid Arthritis (RA), Psoriasis and Inflammatory Bowel Disease (IBD) [6,7,8] It was initially described as a T-cell co-stimulator, and it’s potential in inflammation was immediately recognized [9]. We have recently shown that TL1A together with IL-12, IL-15 and IL-18 induces IL-6 and TNF-a production in leukocytes purified from healthy donors [12]
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