Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5665729 | Current Opinion in Immunology | 2017 | 6 Pages |
â¢CTLA-4 is crucial for quantitative regulation of immune homeostasis and tolerance.â¢LRBA plays a role in maintaining an intracellular pool of CTLA-4 in Tregs and activated T cells.â¢Heterozygous CTLA4 or biallelic LRBA mutations can lead to autoimmune disease in humans but not in mice.â¢CTLA-4 blockade therapy can unleash underlying antitumor or autoimmune responses.â¢The microbiota play a critical role in modulating immune activation thresholds regulated by CTLA-4.
CTLA-4 is a crucial negative regulator of immune responses. Absence of CTLA-4 in mice causes autoimmunity and lethal multiorgan lymphocytic infiltration and tissue destruction. Recently, heterozygous CTLA4 or biallelic LRBA mutations leading to functional CTLA-4 deficiency and autoimmunity have been discovered. LRBA was identified as a novel regulator of steady-state CTLA-4 protein levels in Tregs and activated T cells. CTLA-4 deficiency due to checkpoint blockade cancer immunotherapy has also been found to lead to autoimmune reactions. Studies investigating the variable efficacy and adverse autoimmune responses to checkpoint therapy elucidated a role of the microbiota in promoting antitumor and autoreactive immune responses that are regulated by CTLA-4.