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 6

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Telomerase activity of CD3- and CD2-activated PBTs and LPTs. (a) In PBTs...
Telomerase activity of CD3- and CD2-activated PBTs and LPTs. (a) In PBTs, telomerase activity is induced only by CD3 activation, whereas both anti-CD3 and anti-CD2 activation induces enzymatic activity in LPTs. The level of activity is significantly greater in anti-CD3–stimulated PBTs than in both anti-CD3– and anti-CD2–activated LPTs (*P < 0.05). (b) Display of the telomeric-mediated six-nucleotide ladder. The intensity of expression closely correlates with the level of enzymatic activity seen in a. Freshly isolated PBTs and LPTs were cultured in the absence and presence of CD3 or CD2 mAb for 3 days, after which cells were lysed, amplified, and analyzed either by telomerase activity or Southern blot using a nondenaturing bis-acrylamide gel. 1, lysis buffer control; 2, heat-treated control (anti-CD3–activated PBTs). Each bar represents mean ± SEM of five to seven experiments.