Long-term impact of thymectomy performed in early infancy

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IL-7-induced proliferation of human naive CD4 T-cells relies on continued thymic activity

Publication . Silva, Susana L.; Albuquerque, Adriana S.; Matoso, Paula; Charmeteau-de-Muylder, Bénédicte; Cheynier, Rémi; Ligeiro, Dário; Abecasis, Miguel; Anjos, Rui; Barata, João T.; Victorino, Rui M. M.; Sousa, Ana E.

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 of de novo CD4 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 vitro proliferation 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 of DUSP6, 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.

2017-01-19Journal article

Open access

Autoimmunity and allergy control in adults submitted to complete thymectomy early in infancy

Publication . Silva, Susana L.; Albuquerque, Adriana; Amaral, Andreia J.; Li, Quan-Zhen; Mota, Catarina; Cheynier, Rémi; Victorino, Rui M. M.; Santos, M. Conceição Pereira; Sousa, Ana E.

The contribution of the decline in thymic activity for the emergence of autoimmunity is still debatable. Immune-competent adults submitted to complete thymectomy early in life provide a unique model to address this question. We applied here strict criteria to identify adults lacking thymic activity based on sjTREC levels, to exclude thymic rebound and/or ectopic thymuses. In agreement, they featured severe naïve CD4 T-cell depletion and contraction of T-cell receptor diversity. Notwithstanding this, there was neither increased incidence of autoimmune disease in comparison with age-matched controls nor significant changes in their IgG/IgA/IgM/IgE autoreactivity profiles, as assessed through extensive arrays. We reasoned that the observed relative preservation of the regulatory T-cell compartment, including maintenance of naïve regulatory CD4 T-cells, may contribute to limit the emergence of autoimmunity upon thymectomy. Our findings have implications in other clinical settings with impaired thymic activity, and are particularly relevant to studies of autoimmunity in ageing.

2017Journal article

Open access