p53 negatively regulates intestinal immunity by delaying mucosal T cell cycling
Andreas Sturm, Jugoh Itoh, James W. Jacobberger, Claudio Fiocchi
Andreas Sturm, Jugoh Itoh, James W. Jacobberger, Claudio Fiocchi
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Article Immunology

p53 negatively regulates intestinal immunity by delaying mucosal T cell cycling

Abstract

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.

Authors

Andreas Sturm, Jugoh Itoh, James W. Jacobberger, Claudio Fiocchi

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Figure 9

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Effect of p53 antisense treatment on relative movement of PBTs and LPTs....
Effect of p53 antisense treatment on relative movement of PBTs and LPTs. (a) Treatment with p53 antisense (AS) oligonucleotides increases the relative movement of CD3-activated PBTs by 34% and of CD3-activated LPTs by 65%. (b) Treatment increases the relative movement of CD2-activated PBTs by 45% and of CD2-activated LPTs by 60%. Freshly isolated PBTs and LPTs were cultured in the presence or absence of p53 antisense oligonucleotide, scrambled controls, anti-CD3 mAb, or anti-CD2 mAb and, 3 days later, incubated with 20 μM BrdU and restimulated with the same mAb. Relative movement was calculated as described in Methods. Each line represents the mean ± SEM of five experiments. The relative movement after antisense treatment was significantly higher in both anti-CD3– and anti-CD2–activated PBTs and LPTs than in their respective nontransfected and scrambled controls (P < 0.05).