Few prey specifically try to attract their predator. However, the β cells of the islets of Langerhans in the pancreas do just that, by secreting chemokines to attract islet-specific effector T cells, which then destroy them, according to a paper now published in Nature Medicine.

Type 1 diabetes results from the T cell-mediated autoimmune destruction of insulin-secreting β cells. Early in disease pathogenesis, macrophages and T cells infiltrate the islets and, in combination with pro-inflammatory cytokines including interleukin-1β (IL-1β), tumour necrosis factor (TNF) and interferon-γ (IFN-γ), cause insulitis. T cells are not a normal constituent of islets, so what controls the recruitment of these effector cells to these sites?

In this study, Frigerio and colleagues investigated the involvement of chemokines in the recruitment of T cells to the islets. First, they cultured mouse islets and a β-cell line with pro-inflammatory cytokines, and tested whether this resulted in changes in the chemokine expression profiles of these cells. Cytokine treatment caused the upregulated expression of many chemokines, including CXCL9 and CXCL10 transcripts. So, in the presence of pro-inflammatory cytokines, islets and β cells express higher levels of chemokines that are known to attract activated T cells and macrophages.

The authors then used a transgenic mouse model of type 1 diabetes to test the in vivo role of chemokines in disease pathogenesis. RIP-GP transgenic mice express the glycoprotein (GP) of the lymphocytic choriomeningitis virus (LCMV) under the control of the rat insulin promoter (RIP), which leads to the expression of GP on pancreatic cells. Infection of these mice with LCMV leads to severe insulitis and T cell-mediated β-cell destruction. After infection, an increased level of pro-inflammatory cytokines, chemokines (including CXCL9 and CXCL10) and chemokine receptors (including CXCR3, the receptor for CXCL9 and CXCL10) were detected in the islets of these mice. Immunohistology of pancreatic tissue indicated that β cells were the main source of CXCL10 during insulitis.

So, chemokines are expressed in islets during insulitis, but are T cells attracted to these chemokines? In vitro and in vivo studies showed that LCMV-activated T cells are attracted towards the chemokines that are present in inflamed islets. To investigate which chemokine receptors are involved, Frigerio et al. exposed T cells from LCMV-infected mice to CXCL10 (to desensitize CXCR3 on these cells) before they were cultured with the supernatant from a β-cell line. CXCL10 treatment led to a reduced migratory capacity of T cells towards the supernatants of stimulated β cells, indicating that β-cell chemokines preferentially attract T cells through CXCR3. These observations were confirmed in vivo by studies of RIP-GP mice deficient for CXCR3. In the absence of CXCR3, insulitis, diabetes and hyperglycemia were delayed.

Therefore, in type 1 diabetes, β cells contribute to their own destruction by secreting CXCL9 and CXCL10 which specifically attract CXCR3+ effector T cells to the islets. The authors conclude that CXCR3 might represent a new target for therapeutic intervention early in disease.