The role of CXCL10 expressing B cells in skin inflammation

Inflammatory skin diseases, such as psoriasis and allergic contact dermatitis, affect a large proportion of the population. B cells that suppress inflammation, termed regulatory B cells (Breg), are key contributors to homeostasis and to limiting inflammation at many sites, including the skin. IL-10 is an important regulatory molecule used by Bregs to constrain T cell responses. The mechanisms used by Bregs to interact with their target T cells have not been defined, and no approaches exist to modulate T cell effector functions in skin and other sites via targeting of B cell properties. Our preliminary data show that IL-10+ Bregs express CXCL10, ligand for the chemokine receptor CXCR3. Effector CD4 and CD8 T cells are the main cell types that express CXCR3 and chemotax toward CXCL10. We hypothesize that Bregs produce CXCL10 to ‘lure’ effector/memory T cells into their vicinity and expose them to IL-10 and potentially other Breg molecules, resulting in dampened T cell responses and decreased inflammation. Alternatively, CXCL10 expressed by effector B cells may amplify the immune response through enhanced T cell recruitment and/or augmentation of T cell and B cell activation by facilitating antigen-specific T-B interactions. To test our hypothesis, we propose two specific aims: Aim 1 will test the role of B-cell expressed CXCL10 during skin inflammation using a mouse model with inducible B-cell restricted CXCL10-deficiency. Under Aim 2 we will reveal the (IL-10+ and IL-10–) B cell subsets that produce CXCL10 during skin inflammation as well as determine the effector and regulatory T cell subsets attracted to skin B cell CXCL10. The gained knowledge will allow us to refine strategies to modulate cutaneous T cell responses in inflammation, infection, and cancer through targeting B cell functions.