Living Without a Thymus: Impact on CD4 T Cell Compartment

CD4 T cells play a pivotal role in the immune system by orchestrating and regulating immune responses, acting as conductors and coordinators of the activity of other immune cells. Peripheral CD4 T-cell homeostasis results from a dynamic equilibrium between the continuous replenishment by cells egressing the thymus, where T cells are produced, and peripheral mechanisms involving cell proliferation, survival and differentiation of naïve CD4 T cells into effector/regulatory populations. The thymic output is currently considered essential to maintain repertoire diversity throughout life. On the other hand, peripheral homeostatic mechanisms have been shown to be able to maintain naïve T cell counts. The latter is particularly important to counter-act the progressive decline of thymic activity with aging and the accelerated differentiation of naïve cells into memory/effector cells in the context of chronic infections.

Thymectomy performed during corrective cardiac surgery in early infancy provides an extreme clinical setting to gain insights into T cell homeostasis. To investigate the long-term impact of thymectomy on the CD4 T-cell compartment we studied adults, 30 years after thymus removal in early childhood, alongside healthy age-matched controls. Circulating T-cells were evaluated by spectral flow cytometry, and, in parallel, sort-purified CD4 T cells were used to perform scRNAseq combined with TCR and cell surface protein sequencing (CITE-Seq). For the CITE-seq analysis, we selected naïve/memory markers and CD31, which we have previously shown to identify naïve cells with a higher proliferative capacity in response to IL-7. Our longitudinal analysis of these individuals revealed not only the resilience of the naïve compartment but also points to its expansion. We are currently focusing our analysis on the underlying mechanisms. Ultimately, we expect to provide new insights on human CD4 T cell biology and identify pathways for immune reconstitution.