title: Impairment of non-muscle myosin IIA in human CD4+ T cells contributes to functional deficits in the elderly.
abstract: Physiological aging imposes significant alterations in the repertoire of T cells and all associated functions. Although several studies have reported defects upon antigen-induced activation of T cells during aging, the molecular mechanisms that control T-cell receptor (TCR) downmodulation remain to be fully defined. While previous studies have assessed the role of F-actin in regulating activation-induced TCR internalization, few have delineated the roles of motor proteins, such as non-muscle myosin IIA (NMMIIA). In this study, we describe a series of experiments supporting the hypothesis that effective TCR downmodulation requires not only efficient reorganization of the actin cytoskeleton, but also functional NMMIIA. For the first time, we show that CD4(+) T cells from elderly human donors have dysfunctional NMMIIA that contributes to delaying activation-induced TCR internalization and impairing calcium mobilization. Additionally, our results demonstrate that chemical inhibition of NMMIIA in CD4(+) T cells from young donors also results in complete abrogation of TCR internalization, strongly supporting the fundamental role of NMMIIA in modulating this event. Recent observations that the generation of an efficient T-cell response requires migration prompted us to investigate whether NMMIIA also plays a regulatory role in CD4(+) T-cell migration. We show that chemical inhibition of NMMIIA downmodulates chemotactic migration in CD4(+) T cells from both young and elderly donors. Together, these data demonstrate a significant contribution of dysfunctional NMMIIA to TCR-mediated functional defects during aging.
authors: Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, 4300 West Markham St., Little Rock, AR 72205, USA.
authors: Stefania
authors: S
authors: Cane
authors: Subramaniam
authors: S
authors: Ponnappan
authors: Usha
authors: U
authors: Ponnappan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D003599:Cytoskeleton / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D024507:Nonmuscle Myosin Type IIA / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism
chemical_list: D011948:Receptors, Antigen, T-Cell; D024507:Nonmuscle Myosin Type IIA