title: C/EBPα is dispensable for the ontogeny of PD-1+ CD4+ memory T cells but restricts their expansion in an age-dependent manner.
abstract: Ageing and cancer is often associated with altered T cell distributions and this phenomenon has been suggested to be the main driver in the development of immunosenescence. Memory phenotype PD-1+ CD4+ T cells accumulate with age and during leukemic development, and they might account for the attenuated T cell response in elderly or diseased individuals. The transcription factor C/EBPα has been suggested to be responsible for the accumulation as well as for the senescent features of these cells including impaired TCR signaling and decreased proliferation. Thus modulating the activity of C/EBPα could potentially target PD-1+ CD4+ T cells and consequently, impede the development of immunosenescence. To exploit this possibility we tested the importance of C/EBPα for the development of age-dependent PD-1+ CD4+ T cells as well as its role in the accumulation of PD-1+ CD4+ T cells during leukemic progression. In contrast to earlier suggestions, we find that loss of C/EBPα expression in the lymphoid compartment led to an increase of PD-1+ CD4+ T cells specifically in old mice, suggesting that C/EBPα repress the accumulation of these cells in elderly by inhibiting their proliferation. Furthermore, C/EBPα-deficiency in the lymphoid compartment had no effect on leukemic development and did not affect the accumulation of PD-1+ CD4+ T cells. Thus, in addition to contradict earlier suggestions of a role for C/EBPα in immunosenescence, these findings efficiently discard the potential of using C/EBPα as a target for the alleviation of ageing/cancer-associated immunosenescence.
authors.affiliation: Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark ; Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark ; Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark ; Institute of Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Ida Christine
authors.initials: IC
authors.lastname: Norrie
authors.affiliation: Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark ; Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark ; Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Ewa
authors.initials: E
authors.lastname: Ohlsson
authors.affiliation: Institute of Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Olaf
authors.initials: O
authors.lastname: Nielsen
authors.affiliation: Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark ; Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark ; Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Marie Sigurd
authors.initials: MS
authors.lastname: Hasemann
authors.affiliation: Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark ; Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark ; Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Bo T
authors.initials: BT
authors.lastname: Porse
mesh_terms: D000367:Age Factors; D000375:Aging; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D016922:Cellular Senescence; D018450:Disease Progression; D015870:Gene Expression; D007156:Immunologic Memory; D007938:Leukemia / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000401:mortality; D008213:Lymphocyte Activation; D051379:Mice; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D013154:Spleen / Q000276:immunology / Q000378:metabolism
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D061026:Programmed Cell Death 1 Receptor