p53 negatively regulates intestinal immunity by delaying mucosal T cell cycling

To mount an effective immune response, T cells must divide in response to antigen contact.To maintain tolerance, mucosal lamina propria T cells (LPTs) may adapt their cycling to an antigen-rich gut stimulatory environment.Here, we compared the cell cycle kinetics of LPTs and peripheral blood T cells (PBTs) before and after CD3-and CD2-mediated activation.While CD3-activated naive (CD45RA + ) and memory (CD45RO + ) PBTs peaked in the S and G2/M phase at 2-3 days, CD3-activated LPTs peaked at 4-6 days.In contrast, CD2 activation induced modest PBT but vigorous LPT cycling.The doubling time of CD3-activated PBTs was 1 day, while that of CD3-or CD2-activated LPTs was 2 days.LPTs failed to upregulate cyclin-dependent kinase 4 and cyclin D3, but Rb phosphorylation and cyclin A and B1 upregulation were induced by CD2 engagement.The extents of clonal expansion in LPT and PBT were comparable, indicating that LPTs' slow replication delays but does not hinder cell division.CD2-activated LPTs displayed a striking upregulation of p53, whose blockade by antisense oligonucleotides accelerated their S phase transit time to that of CD3-activated PBTs.By slowing LPT cycling, p53 may act as a negative regulator of mucosal immunity, promoting immunological tolerance by preventing excessive T cell replication.