The present study shows that young adults who were thymectomized within 2 weeks of birth display a number of immunological alterations, including lower CD4+
T cell counts, reduced proportions of recent thymic emigrants and naive cells, accumulation of oligoclonal memory T cell populations (including highly differentiated CD57+
cells), and increased markers of inflammation. The occurrence of such changes is normal with age, but it is usually observed much later during life. Our results therefore indicate that YATECs can have premature signs of immune aging and that the phenomenon of immunosenescence is strongly related to the lack of thymic activity and inadequate production of new T cells, independently of age. Future studies are needed to gain insight into the increase of proinflammatory cytokines in YATECs, to understand its relationship to altered homeostasis and a disequilibrium between lymphocyte subsets in these donors. For instance a number of studies suggest a role for regulatory T cells in maintaining intestinal homeostasis (32
). An imbalance between regulatory and effector cells may thus affect the control of inflammation in the gastrointestinal tract area, potentially leading to the rise of proinflammatory markers. It is important to note that the absence of thymus appeared to have no adverse consequence on memory T cell generation and the functional attributes of antigen specific T cells, at least within 20–25 years following thymectomy. This may account for the lack of clinical symptoms despite apparent immunological alterations at the level of T cell production in YATECs.
Despite their young age, a number of YATECs (32%) presented particularly marked alterations in the T cell compartment that are distinctive of individuals older than 75 years. These alterations (i.e., profound imbalance between naive and memory T cell proportions, loss of T cell repertoire diversity, evidence of inflammation) are reminiscent of the immune risk phenotype, which is defined by gerontologists as a cluster of immune measures that are predictive of early all-cause mortality in the elderly (33
). Although all YATECs enrolled in the present study (including those with severe immunological alterations) were clinically asymptomatic, such phenotype is suggestive of a certain degree of immune fragility in this subgroup of YATECs. Of note, recent data suggest that thymectomized children present delayed antibody responses to tick-borne encephalitis vaccination (35
). The demise of the thymus in the elderly is considered a major causative factor of declining immune competence (2
). Moreover, it is known that continuous T cell renewal is crucial for the maintenance of effective immunity (37
). Last, loss of TCR repertoire diversity has been shown to contribute to diminished immune responsiveness (38
). Due to their relatively young age, it is likely that YATECs have only been exposed to a limited number of pathogens, against which their initial immune resources have been sufficient, so that it may be too early to document adverse clinical outcomes. Nonetheless, the consequences of thymectomy on patients’ health are likely to arise earlier than normally anticipated, in relation to a reduced capacity to mount effective adaptive immune responses to new pathogens.
The occurrence of such a marked phenotype was directly associated with the development of a strong T cell response against CMV. This finding is in line with data from murine studies suggesting that, in the absence of thymic contribution, the pool of naive T cells wanes, eventually leaving antigen-experienced T cells to fill the immunological space. In these conditions, the T cell repertoire is thus shaped by the response (i.e., T cell activation, expansion, or death) to antigens (self or foreign) (40
). In this context, infection by CMV is particularly relevant: although it is asymptomatic in most immunocompetent subjects, it is known to induce a massive expansion of CMV-specific T cells, reaching up to 40% of total T cells during chronic infection (31
). This phenomenon is also known as memory inflation (43
) and was recently shown to be maintained by a continuous replacement of short-lived CMV-specific T cells through the recruitment of naive T cells in the murine CMV infection model (45
). Together, these findings indicate that in order to cope with the strong pressure imposed by CMV, the cellular immune system prematurely exhausts its resources in the context of lack of adequate thymic output. Although CMV infection is usually considered benign, it has been proposed to play an important role in the development of immunosenescence (46
). Our data highlight the impact of this virus on the immune system and potential consequences on immune integrity in particular contexts such as the absence of thymus. This may account at least partially for the association between CMV infection and early mortality in elderly (47
) or for more rapid disease progression in HIV co-infected patients (48
), settings characterized by a lack of adequate T cell renewal.
Importantly, since CMV prevalence is high in the general population (50% to 80%), a large number of CHD patients is at risk of developing significant immunological alterations. Considerate immune and clinical check-ups of thymectomized CHD patients may therefore be advised to monitor the development of an immune risk phenotype and potentially related illnesses. Moreover, approaches to boost residual thymic activity and reconstitute the naive T cell compartment in thymectomized CHD patients may be considered. In this context, IL-7, a cytokine that plays an important role in modulating thymic output and the expansion of naive and memory cells may represent an interesting perspective for YATECs (49
). Indeed, recent studies show that administration of rhIL-7 increases in vivo
TCR repertoire diversity through the preferential expansion of naive T cells in healthy individuals (51
) as well as in lymphopenic HIV-infected patients (52
). Last, surgeons are highly recommended to preserve as much thymic tissue as possible when performing interventions in newborns with CHD. The maintenance of thymic activity and T cell diversity is necessary to prevent the premature development of an immune risk phenotype as these patients age and as pathogens challenge their immune system.