Molecular mimicry is not a sufficient cause of autoimmune liver disease in mice

Question A prevalent concept to explain the occurrence of autoimmunity is cross-recognition of microbial and self-antigens, i.e. molecular mimicry. However, the actual role of molecular mimicry in disease development remains controversial. While it is suggested to activate autoreactive T cells, it might also induce a suppressive response, such as by Tregs and thus protect from autoimmune disease.

Methods We have previously generated a mouse model in which an MHC class II-restricted CD4 T cell epitope of LCMV (GP61-80) is expressed in hepatocytes (Alb-iGP). Alb-iGP mice do not develop autoimmune liver disease (ALD); however, when crossed to Smarta mice featuring T cells recognizing GP61-80, the resulting Alb-iGP_Smarta mice spontaneously develop ALD after 20 weeks of age. To study the harmful or protective effects of molecular mimicry, we infected Alb-iGP and Alb-iGP_Smarta mice at 8 weeks of age with 10⁶ FFU LCMV-WE, monitored the incidence of ALD and analyzed the GP61-80-specific T cell response.

Results Following viral clearance, Alb-iGP mice maintained an enlarged population of antigen-specific CD4 T cells in liver (0.75 % vs. 0.09 %) and spleen (0.60 % vs. 0.05 %) up to the age of 52 weeks as compared to non-infected controls. Despite the presence of potentially autoreactive CD4 T cells, these mice did not develop ALD. ALD resistance was associated with Treg expansion that amounted to 25 % of antigen-specific T cells in the liver as compared to 5 % Tregs in non-specific CD4 T cells. In contrast, ALD-prone Alb-iGP_Smarta mice remained chronically infected, presumably due to reduced CD8 T cell numbers, but were protected from ALD. Similar to Alb-iGP mice, ALD resistance of infected Alb-iGP_Smarta mice was associated with a 5-fold increase in antigen-specific Tregs and reduction of antigen-specific CD4 effector T cells as compared to non-infected controls; moreover, the remaining effector cells displayed an exhausted phenotype.

Conclusion Acute infection of Alb-iGP mice induced lasting expansion of potentially self-reactive CD4 T cells. However, these mice were protected from ALD, presumably due to a high proportion of antigen-specific Tregs. Chronic viral infection of Alb-iGP_Smarta mice was accompanied with T cell exhaustion, a loss of antigen-specific effector T cells and an increase in antigen-specific Tregs, which prevented development of ALD. Thus, molecular mimicry provoked a suppressive response and was thus not a sufficient cause of ALD in mice.

Publication History

Article published online:
04 January 2021