Enhanced B-1 self-renewal and attenuated atherosclerotic lesion development in Cd19^cre/+Ldlr^-/- mice on Western-type...

We previously reported that one Cd19 allele inactivation by insertion of the Cre-expressing cassette specifically impairs the development of B1a and marginal zone B (MZB) cells but enhances humoral responses in vivo. Because B1 and MZB cells are considered atheroprotective, this study aims to investigate the potential impact of Cd19 haplodeficiency on atherosclerosis.

Cd19^cre/+ and Cd19^+/+ littermates on Ldlr^-/- background were generated and fed Western-type diet (WTD) to induce atherosclerosis. ELISA/Q-PCR, flow cytometry, adoptive transfer experiments and immunohistochemistry were employed to determine the development, phenotype and function of B cells as well as atherosclerotic lesion development.

Upon WTD-feeding, Cd19^cre/+Ldlr^-/- mice developed significantly smaller lesions, albeit the comparable plasma levels of total cholesterol, IgM and IgG. MZB cells remained constantly lower, while the number of B1 cells in spleens significantly increased in WTD-fed Cd19^cre/+Ldlr^-/- mice, likely due to the increased proliferative capacities. Moreover, an increase of B1 cells was evident in thoracic aortic perivascular adipose tissues (PVAT) with higher expressions of secreted IgM and IL-10. Furthermore, Cd19 haplodeficiency significantly promoted the expressions of IL-10, PD-L1 and TGF-β1 in B1 cells, and thereby augmented the differentiation of IL-10-expressing Tr1 and Foxp3⁺ Treg cells in spleens and aortic lymph nodes, eventually leading to reduced T cell accumulations in atherosclerotic vessels.

Cd19 haplodeficiency by knock-in Cre in Cd19^cre/+Ldlr^-/- mice significantly impacts atherosclerotic lesion development likely via B1 cells, and thus Cd19^cre/+ mice on atherosclerosis-prone background should be chosen as critical controls when the Cd19-Cre/loxp system is employed in such studies.