Bim dictates naive CD4 T cell lifespan and the development of age-associated functional defects.
With age, peripheral naive CD4 T cells become both longer lived and functionally impaired and they express reduced levels of Bim, a proapoptotic Bcl family member. In this study, we show that reduced Bim expression by naive CD4 T cells intrinsically mediates their longer lifespan in the periphery. Moreover, using mixed bone marrow chimeras reconstituted with Bim(+/+) and Bim(+/-) bone marrow cells, Bim(+/-) naive CD4 T cells exhibit accelerated development of age-associated dysfunctions, including reduced proliferation and IL-2 production and defective helper function for B cells, without any increase in their turnover. However, newly generated Bim(+/-) naive CD4 T cells in middle-aged mice are not defective, indicating an additional requirement for their persistence in the periphery. These age-associated immune defects develop independently of the "aged" host environment and without extensive division, distinguishing them from classic "senescence." We suggest that the reduction of Bim levels with age in naive CD4 T cell is the initiating step that leads to increased cellular lifespan and development of age-associated functional defects.
Tsukamoto
Hirotake
H
Trudeau Institute, Saranac Lake, NY 12983, USA.
Huston
Gail E
GE
Dibble
John
J
Duso
Debra K
DK
Swain
Susan L
SL
D019264:Adoptive Transfer; D000375:Aging / Q000276:immunology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000276:immunology / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002469:Cell Separation; D002470:Cell Survival / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins