IL-7-Induced Proliferation of Human Naive CD4 T-Cells Relies on Continued Thymic Activity

Abstract

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.

Major CD4 T-Cell Depletion and Immune Senescence in a Patient with Chronic Granulomatous Disease

“…Moreover, it resembles the profile of immunosenescence documented in individuals thymectomized early in life during corrective cardiac surgery (26, 30, 31). …”

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

“…This occurred despite these individuals featured marked contraction of the conventional naïve T-cell pool and a restricted T cell-receptor diversity[16]. 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.…”

“…Thymectomized individuals were selected based on severely reduced sjTRECs/μl[15, 16] at the time of our evaluation (July 2011—October 2012).…”

“…Importantly, in contrast to other studies[3, 4], we specifically excluded individuals with evidence of remaining thymic activity, based on single-joint T-cell receptor excision circle (sjTREC) quantification[15, 16]. sjTRECs are by-products of TCR rearrangements during T-cell development in the thymus that are enriched in recent-thymic emigrants and progressively lost as cells divide in the periphery[17].…”

Cell generation dynamics underlying naïve T cell homeostasis in adult humans

“…Two previous studies have reported that CD4 + CD31naïve T cells may have limited proliferative potential to IL-7 in vitro [41,42]. It remains unclear, however, whether differences exist for each population in vivo, and no attempts have been made, to our knowledge, to measure the proliferation of each population using markers that exclude contaminating memory populations in the naïve T cell pool.…”