Date Published: July 7, 2017
Publisher: Public Library of Science
Author(s): Susana L. Silva, Adriana Albuquerque, Andreia J. Amaral, Quan-Zhen Li, Catarina Mota, Rémi Cheynier, Rui M. M. Victorino, M. Conceição Pereira-Santos, Ana E. Sousa, Pierre Bobé.
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.
The thymus is essential to the establishment of the “peripheral” T-cell compartment before birth and during the accelerated somatic growth of childhood, and contributes to its continuous replenishment until at least the sixth decade of life. Thymus removal early in infancy during corrective cardiac surgery is, therefore, associated with marked contraction of the naïve T-cell subset, as well as with the presence of markers of premature immune senescence, as a result of homeostatic naïve T-cell proliferation/differentiation[1, 2]. This is thought to occur mainly in response to self and environmental antigens, raising the question whether early thymectomy leads to an increased risk of autoimmunity and/or allergic disease. The few studies available are not conclusive[3–8]. The discrepant results may be in part due to cohort heterogeneity regarding age, length of follow-up post-thymectomy and degree of residual thymic activity[3–8]. Notably, thymic recovery has been reported in some individuals [9, 10].
We compared our cohort of adults with strictly defined complete thymus removal in early infancy with age-matched healthy individuals (Table 1). Thymectomized individuals were selected based on severely reduced sjTRECs/μl[15, 16] at the time of our evaluation (July 2011—October 2012).
Adults with complete thymectomy early in infancy featured very low naïve CD4 and CD8 T-cell counts (Table 1), as expected[4, 5, 7, 8, 24–26]. Importantly, their Treg compartment was preserved, with evidence of similar expression levels of markers associated with suppressive function phenotype within memory-Tregs, based on FoxP3, CTLA-4 and CD39 expression levels [27, 28](Table 1).
Our study, that was strictly designed to include only adults without evidence of thymic activity upon thymus removal in infancy, revealed no increase of clinical/subclinical manifestations of allergy or of autoimmune diseases, as compared with a group of age matched healthy individuals. This occurred despite these individuals featured marked contraction of the conventional naïve T-cell pool and a restricted T cell-receptor diversity. It is likely that the absence of autoimmune manifestations may be related to the parallel preservation of the Treg compartment, given the major role of regulatory T-cells in their control. Notably, the thymus-committed naïve-Treg population was found to be maintained in these adults by peripheral homeostatic mechanisms, despite the lack of thymic output since early in infancy. Naïve-Tregs are considered to play a major role in the control of self-reactivity due to their enrichment in self-reactive T-cell receptors.