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.
Sturm
Andreas
A
Division of Gastroenterology, Department of Medicine, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4952, USA.
Itoh
Jugoh
J
Jacobberger
James W
JW
Fiocchi
Claudio
C
D015153:Blotting, Western; D018801:CD2 Antigens / Q000096:biosynthesis; D017252:CD3 Complex / Q000096:biosynthesis; D002453:Cell Cycle; D002455:Cell Division; D019925:Cyclin A / Q000096:biosynthesis; D019926:Cyclin B / Q000096:biosynthesis; D056744:Cyclin B1; D005434:Flow Cytometry; D016195:G2 Phase; D016158:Genes, p53 / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008938:Mitosis; D009092:Mucous Membrane / Q000276:immunology*; D016376:Oligonucleotides, Antisense / Q000378:metabolism / Q000494:pharmacology; D010641:Phenotype; D012313:RNA / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000096:biosynthesis; D012260:Ribonucleases / Q000378:metabolism; D016196:S Phase; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019098:Telomerase / Q000378:metabolism; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D015854:Up-Regulation
C534699:CCNB1 protein, human; D018801:CD2 Antigens; D017252:CD3 Complex; D019925:Cyclin A; D019926:Cyclin B; D056744:Cyclin B1; D006657:Histones; D016376:Oligonucleotides, Antisense; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D012313:RNA; D019098:Telomerase; D012260:Ribonucleases; D017493:Leukocyte Common Antigens