Spatial distribution, kinetics, signaling and cytokine production during homeostasis driven proliferation of CD4+ T cells.
During recovery from lymphopenia, the naïve T-cells undergo homeostasis driven proliferation (HDP) and acquire a memory phenotype. The HDP of T-cells requires signals derived from T-cell-receptor, p56lck kinase, IL-7R and IL-15R. However, the role of other signaling molecules during HDP of CD4+ T-cells remains speculative. The differentiation of naïve T-cells into Th1/Th2/Th17 or Treg populations during HDP is not well understood. Present report describes the spatial and signaling characteristics of HDP of CD4+ T-cells and their cytokine profiles. The HDP of CD4+ T-cells was found to occur only in specific areas (T-cell zones) of secondary lymphoid organs of lymphopenic mice. The inhibitors of MEK and PKC and their combination with inhibitors of PI3kinase and mTOR suppressed mitogen induced T-cell proliferation without affecting their HDP. The CD4+ T-cells taken from reconstituted lymphopenic mice showed activation of proteins involved in NF-kappaB pathway, significantly higher production of pro-inflammatory cytokine IL-6, and lower production of IL-4 as compared to T-cells from normal mice. Plumbagin, a known NF-kappaB blocker inhibited survival as well as HDP of CD4+ T-cells and IL-6 production in activated T-cells. Our results demonstrate the essential role of NF-kappaB during HDP of T-cells.
Sharma
Deepak
D
Radiation Biology & Health Sciences Division, Bio-Medical Group, Bhabha Atomic Research Centre, Modular Laboratories, Trombay, Mumbai 400085, India.
Kumar
S Santosh
SS
Checker
Rahul
R
Raghu
Rashmi
R
Khanam
Shazia
S
Krishnan
Sunil
S
Sainis
Krishna Balaji
KB
D000818:Animals; D001202:Ascitic Fluid / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D006706:Homeostasis / Q000276:immunology*; D007156:Immunologic Memory; D007700:Kinetics; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008231:Lymphopenia / Q000276:immunology / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009285:Naphthoquinones / Q000494:pharmacology; D010529:Peritoneal Cavity / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology / Q000473:pathology
D016207:Cytokines; D016328:NF-kappa B; D009285:Naphthoquinones; D011493:Protein Kinase C; D020930:MAP Kinase Kinase Kinases; C014758:plumbagin