IL-7-Induced Proliferation of Human Naive CD4 T-Cells Relies on Continued Thymic Activity.
Naive CD4 T-cell maintenance is critical for immune competence. We investigated here the fine-tuning of homeostatic mechanisms of the naive compartment to counteract the loss ofde novoCD4 T-cell generation. Adults thymectomized in early childhood during corrective cardiac surgery were grouped based on presence or absence of thymopoiesis and compared with age-matched controls. We found that the preservation of the CD31-subset was independent of the thymus and that its size is tightly controlled by peripheral mechanisms, including prolonged cell survival as attested by Bcl-2 levels. Conversely, a significant contraction of the CD31+naive subset was observed in the absence of thymic activity. This was associated with impaired responses of purified naive CD4 T-cells to IL-7, namely,in vitroproliferation and upregulation of CD31 expression, which likely potentiated the decline in recent thymic emigrants. Additionally, we found no apparent constraint in the differentiation of naive cells into the memory compartment in individuals completely lacking thymic activity despite upregulation ofDUSP6, a phosphatase associated with increased TCR threshold. Of note, thymectomized individuals featuring some degree of thymopoiesis were able to preserve the size and diversity of the naive CD4 compartment, further arguing against complete thymectomy in infancy. Overall, our data suggest that robust peripheral mechanisms ensure the homeostasis of CD31-naive CD4 pool and point to the requirement of continuous thymic activity to the maintenance of IL-7-driven homeostatic proliferation of CD31+naive CD4 T-cells, which is essential to secure T-cell diversity throughout life.
Faculdade de Medicina, Instituto de Medicina Molecular, Universidade de Lisboa, Lisboa, Portugal; Centro Hospitalar de Lisboa Norte, Hospital de Santa Maria, Lisboa, Portugal.
Susana L
SL
Silva
Faculdade de Medicina, Instituto de Medicina Molecular, Universidade de Lisboa , Lisboa , Portugal.
Adriana S
AS
Albuquerque
Faculdade de Medicina, Instituto de Medicina Molecular, Universidade de Lisboa , Lisboa , Portugal.
Paula
P
Matoso
Cytokines and Viral Infections, Immunology Infection and Inflammation Department, Institut Cochin, INSERM, U1016, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Paris, France.
Bénédicte
B
Charmeteau-de-Muylder
Cytokines and Viral Infections, Immunology Infection and Inflammation Department, Institut Cochin, INSERM, U1016, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Paris, France.
Rémi
R
Cheynier
Centro de Sangue e Tranplantação de Lisboa, Instituto Português de Sangue e Transplantação, IP , Lisboa , Portugal.
Dário
D
Ligeiro
Departamento do Coração, Hospital de Santa Cruz, Centro Hospitalar de Lisboa Ocidental , Carnaxide , Portugal.
Miguel
M
Abecasis
Departamento do Coração, Hospital de Santa Cruz, Centro Hospitalar de Lisboa Ocidental , Carnaxide , Portugal.
Rui
R
Anjos
Faculdade de Medicina, Instituto de Medicina Molecular, Universidade de Lisboa , Lisboa , Portugal.
João T
JT
Barata
Faculdade de Medicina, Instituto de Medicina Molecular, Universidade de Lisboa, Lisboa, Portugal; Centro Hospitalar de Lisboa Norte, Hospital de Santa Maria, Lisboa, Portugal.
Rui M M
RM
Victorino
Faculdade de Medicina, Instituto de Medicina Molecular, Universidade de Lisboa , Lisboa , Portugal.
Ana E
AE
Sousa
IL-7; T-cell homeostasis; naive CD4 T-cells; thymectomy; thymus