title: Peripheral residence of naïve CD4 T cells induces MHC class II-dependent alterations in phenotype and function.
abstract: BACKGROUND
  As individual naïve CD4 T lymphocytes circulate in the body after emerging from the thymus, they are likely to have individually varying microenvironmental interactions even in the absence of stimulation via specific target recognition. It is not clear if these interactions result in alterations in their activation, survival and effector programming. Naïve CD4 T cells show unimodal distribution for many phenotypic properties, suggesting that the variation is caused by intrinsic stochasticity, although underlying variation due to subsets created by different histories of microenvironmental interactions remains possible. To explore this possibility, we began examining the phenotype and functionality of naïve CD4 T cells differing in a basic unimodally distributed property, the CD4 levels, as well as the causal origin of these differences.
  
  
  RESULTS
  We examined separated CD4hi and CD4lo subsets of mouse naïve CD4 cells. CD4lo cells were smaller with higher CD5 levels and lower levels of the dual-specific phosphatase (DUSP)6-suppressing micro-RNA miR181a, and responded poorly with more Th2-skewed outcomes. Human naïve CD4lo and CD4hi cells showed similar differences. Naïve CD4lo and CD4hi subsets of thymic single-positive CD4 T cells did not show differences whereas peripheral naïve CD4lo and CD4hi subsets of T cell receptor (TCR)-transgenic T cells did. Adoptive transfer-mediated parking of naïve CD4 cells in vivo lowered CD4 levels, increased CD5 and reactive oxygen species (ROS) levels and induced hyporesponsiveness in them, dependent, at least in part, on availability of major histocompatibility complex class II (MHCII) molecules. ROS scavenging or DUSP inhibition ameliorated hyporesponsiveness. Naïve CD4 cells from aged mice showed lower CD4 levels and cell sizes, higher CD5 levels, and hyporesponsiveness and Th2-skewing reversed by DUSP inhibition.
  
  
  CONCLUSIONS
  Our data show that, underlying a unimodally distributed property, the CD4 level, there are subsets of naïve CD4 cells that vary in the time spent in the periphery receiving MHCII-mediated signals and show resultant alteration of phenotype and functionality via ROS and DUSP activity. Our findings also suggest the feasibility of potential pharmacological interventions for improved CD4 T cell responses during vaccination of older people via either anti-oxidant or DUSP inhibitor small molecules.
authors.affiliation: National Institute of Immunology, New Delhi, 110067, India. sanketrn@nii.ac.in.
authors.forename: Sanket
authors.initials: S
authors.lastname: Rane
authors.affiliation: National Institute of Immunology, New Delhi, 110067, India. rituparna.das@yale.edu.|Current address: Yale Cancer Center, Sterling Hall of Medicine, New Haven, USA. rituparna.das@yale.edu.
authors.forename: Rituparna
authors.initials: R
authors.lastname: Das
authors.affiliation: National Institute of Immunology, New Delhi, 110067, India. vrangana@uhnresearch.ca.|Current address: Division of Genetics & Development, Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada. vrangana@uhnresearch.ca.
authors.forename: Vidya
authors.initials: V
authors.lastname: Ranganathan
authors.affiliation: National Institute of Immunology, New Delhi, 110067, India. savit@thsti.res.in.|Current address: Pediatric Biology Centre, Translational Health Sciences and Technology Institute, Gurgaon, India. savit@thsti.res.in.
authors.forename: Savit
authors.initials: S
authors.lastname: Prabhu
authors.affiliation: National Institute of Immunology, New Delhi, 110067, India. arundhoti@nii.ac.in.
authors.forename: Arundhoti
authors.initials: A
authors.lastname: Das
authors.affiliation: National Institute of Immunology, New Delhi, 110067, India. mattoo.hamid@mgh.harvard.edu.|Current address: MGH Cancer Center, Charlestown, USA. mattoo.hamid@mgh.harvard.edu.
authors.forename: Hamid
authors.initials: H
authors.lastname: Mattoo
authors.affiliation: Department of Biological Sciences, University of Arkansas, Fayetteville, Arkansas, USA. jdurdik@uark.edu.
authors.forename: Jeannine Marie
authors.initials: JM
authors.lastname: Durdik
authors.affiliation: National Institute of Immunology, New Delhi, 110067, India. anna@nii.res.in.
authors.forename: Anna
authors.initials: A
authors.lastname: George
authors.affiliation: National Institute of Immunology, New Delhi, 110067, India. satyajit@nii.res.in.
authors.forename: Satyajit
authors.initials: S
authors.lastname: Rath
authors.affiliation: National Institute of Immunology, New Delhi, 110067, India. vineeta@nii.res.in.
authors.forename: Vineeta
authors.initials: V
authors.lastname: Bal
mesh_terms: D000328:Adult; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002478:Cells, Cultured; D054642:Dual Specificity Phosphatase 6 / Q000235:genetics / Q000378:metabolism; D005240:Feasibility Studies; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D055815:Young Adult
chemical_list: D000949:Histocompatibility Antigens Class II; D035683:MicroRNAs; C529102:Mirn142 microRNA, mouse; D017382:Reactive Oxygen Species; D011948:Receptors, Antigen, T-Cell; C529100:mirn181 microRNA, mouse; C517035:DUSP6 protein, human; D054642:Dual Specificity Phosphatase 6; C517036:Dusp6 protein, mouse