Highlight of 2023: Tregs in the lungs

In this article for the Highlights of the 2023 Series, we discuss recent discoveries on regulatory T cells in the lungs and their multifaceted roles in various contexts. Key advancements in Treg immunology have broadened our understanding of lung tissue homeostasis and the potential role of Tregs in pathological processes. As a barrier surface, the lung is constantly exposed to foreign agents able to solicit inflammatory reactions. This context indicates the potential role for Foxp3+ regulatory T cells (Tregs), as the key immune cells governing inflammation shutdown. In 2023, several key papers have highlighted the capacity of lung Tregs to mediate tissue repair and to modulate the lung environment in response to self-antigen versus foreign antigen (Figure 1). Here, we discuss four papers from 2023 on the molecular mechanisms underlying Tregs function and the physiological significance of Tregs in the lung. Like other T cell subsets, Tregs rely on antigen recognition through the T cell receptor (TCR) for engagement of activation and function. The paper by Shin et al. demonstrated the utility of self-antigens in the lung tissue to activate self-reactive Tregs for tissue homeostasis.1 The authors generated a novel transgenic mouse (CC10-USA), in which the neo-self-antigens of 2W and gp66 were expressed by club cells, restricting expression to the lung tissue. Modeling autoimmune disease, gp66-reactive neo-self-antigen-specific T cells were transferred into the transgenic mice, resulting in expanded autoreactive T cells and lung tissue damage. During the inflammatory response against gp66, endogenous 2W-reactive CD4+Foxp3+ T cells were elevated, demonstrating the capacity of distinct neo-self-reactive Tregs to control the autoimmune response. Selective blocking of the TCR or IL-2 severely reduced this population of neo-self-antigen-specific Tregs, identifying key molecular dependencies for this reaction. In 2023, the work of Yamada et al. demonstrated the therapeutic potential of lung Tregs in organ transplantation.2 The study showed that mice pre-treated with IL-2/JES6-1 antibody complexes (selective for the high affinity IL-2 receptor, CD25, preferentially expressed by Tregs) before lung transplantation maintained the grafted lung and its function, such as gas exchange, while untreated mice underwent graft rejection. While this effect could be mediated through the systemic expansion observed in the circulating Treg population, there were indications in the data that the transplant-resident population contributed to tolerance. The IL-2/JES6-1 treated transplanted mice developed tertiary lymphoid structures (iTLS), localized near smooth muscle actin bronchi, with a rich mixture of leukocytes, including the expanded Treg population. While these structures developed in all transplanted mice, in the absence of IL-2 treatment, or following the depletion of Tregs, the iTLS disappeared within weeks, coupled with graft rejection. The research on Treg-rich TLS suggests a novel sub-anatomical compartment that can influence decisions of immunity versus tolerance. In our first two highlights, we selected papers demonstrating lung Treg control of anti-self responses. In our final two, we look at lung Treg control over disease caused by infection. Xu et al. investigated the role of lung Tregs in a bacterial infection model of pneumococcal pneumonia.3 The use of the Foxp3DTR/EGFP system allowed a comparison of Treg-deficient mice and wildtype upon exposure to Streptococcus pneumoniae. In wildtype mice, the elevated levels of TNF-α in the lung during infection activated the Treg population expressing TNFRII (TNFR2+ Tregs). This activation led to the dampening of γδT cells expressing IL-17A (γδT17), protecting against tissue damage. Mice lacking Tregs, or TNFR2−/− mice, demonstrated enhanced γδT17 activation, elevated neutrophilic infiltration and extensive lung damage. However, transferring TNFR2+ Treg cells to TNFR2−/− mice restored the immune control, demonstrating the counter-inflammatory response of Tregs during bacterial infection was mediated by TNF-α sensing directly by the Treg population. The paper demonstrates the versatility of the lung Treg population, utilizing different signals for expansion in response to different types of inflammation. The return to homeostasis and tissue regeneration following infection is a key stage of tissue immunity, for which Tregs have a prominent role.4, 5 In our final highlight paper, Kaiser and colleagues unveiled a molecular mediator used by Tregs to drive tissue repair after viral influenza infection.6 In their paper, Tregs are shown to engage Collagen-14+ expressing epidermal growth factor receptor (Col14a1+EGFR) mesenchymal cells by producing amphiregulin (Areg). This population in turn activates regeneration of the alveolar structure through support of the precursor alveolar type 2 epithelial cell (AT2) population. In the study, mice infected with influenza displayed an accumulation of Areg-producing Tregs near infected sites. Through knockout experiments, with selective deletion on Tregs or total T cells (Aregfl/flFoxp3YFP-cre and Aregfl/flCD4-Cre mice, respectively), Areg derived from Tregs proved indispensable for alveolar regeneration and their function in gas exchange. The authors further demonstrated the critical mesenchymal intermediate in this pathway, with the Col14+ subset of mesenchymal cells exhibiting higher EGFR (the receptor for Areg) levels and converting this signal into fibroblast growth factor production to act on the alveolar precursor niche. This cellular intermediate was validated during organoid culture experiments, where the absence of mesenchymal cells or the deletion of EGFR on mesenchymal cells altered alveolar differentiation. These 2023 papers on lung Tregs highlight the importance of Tregs in dampening inflammation and driving tissue repair in models of autoimmunity, transplant rejection, bacterial infection and post-viral repair. From the steady state to diverse disease settings, lung Tregs have multifaceted functions, responding to diverse stimuli and using multiple effector pathways to aid return to homeostasis. Together, these papers offer a pathway toward exploiting lung Tregs across different respiratory challenges. The authors declare no conflicts of interest. Ntombizodwa Makuyana: Conceptualization; writing – original draft; writing – review and editing. Adrian Liston: Conceptualization; writing – original draft; writing – review and editing.