Investigation of the role of atypical chemokine receptors CCRL1 and CCRL2 in antibody aesponses and the battle of the CARs: CD28 costimulatory endodomains endow T Cells with more robust effector functions in vitro compared to their 4-1BB counterparts

摘要

Project 1:udCC-Chemokine receptor-like 1 (CCRL1) and 2 (CCRL2) are members of the atypical chemokine receptor family. Little is known about the role of these receptors in the antibody response. Mice doubly deficient in CCRL1 and CCRL2 showed no abnormalities in cell localisation in the spleen or lymph nodes and no difference in antibody titres following thymus-dependent (TD) immunisation. However, IgM and IgG3 titres were increased in the thymus-independent 2 response. In the spleen, B cell numbers were increased at rest, but normal after TD immunisation; while in lymph nodes B cell numbers were decreased both before and after TD immunisation.udProject 2:udChimeric antigen receptors (CARs) combine MHC-independent antigen recognition with T cell effector functions. Second generation CARs encompass a costimulatory endodomain to enhance T cell activation and survival. So far, it is not known whether CD28-containing CARs or 4-1BB-containing CARs provide T cells with favourable responses. Therefore, we compared these two constructs for the in vitro functional T cell output they provide. CD28-CAR+ T cells produced superior IFN-γ and degranulation responses, but 4-1BB-CAR+ T cells showed a greater resistance to apoptosis. Together, these data suggest the CD28-CAR is favourable, showing greater IFN-γ and cytotoxic responses, despite the greater propensity for apoptosis.