The immune system is efficient at protecting the host against a wide diversity of dangers (tumors, viruses, bacteria and parasites). Its efficacy lies in its adaptability, allowing it to tailor responses based on the nature of the danger. CD4 T lymphocytes, which orchestrate immune responses, exhibit remarkable functional plasticity; according to environmental cues, they activate distinct gene networks adjusting their phenotype and functions. Consequently, CD4 T cells can differentiate into diverse T helper (Th) cell subsets, crucial for effective immune responses.

Our recent findings demonstrate that in Th2 cells, transcriptional specificity is largely determined by a restricted set of endogenous retroviruses that have been exapted into cis-regulatory activator modules. Expanding on this, our study delves into the broader impact of transposable elements (TEs) on genomic architecture shaping T cell identity. Integrating transcriptomic and epigenetic analyses, we find that TE-derived sequences contribute significantly to the coordination of CD4 T cell programming. Notably, in Th1 cells, pivotal for host defense against cancer or viral infections, a substantial fraction of Tbet binding sites, master regulator of the lineage, originates from LINE2 TEs. These TEs likely integrated into the genome before mammalian radiation, In the course of evolution, the 5' region of LINE2 has degenerated, yet the Tbet motif persists within CD4 enhancers adjacent to vital immune genes, offering advantageous properties to the cell.

Furthermore, TE-mediated recruitment of Kruppel-associated box zinc finger proteins (KZFPs) appears to repress enhancers associated with alternative cell fates, maintaining Th cell lineage stability. Different TE families seem to restrict T cell plasticity by recruiting transcriptional repressors, thereby reinforcing specific lineage programs.

In summary, our data underscore the evolutionary co-option of certain transposable elements in shaping and perpetuating T cell integrity, both by the introduction of immune TFBS in the T(h)-cis regulatory elements and controling their epigenetic state and function.