Date of Award
Doctor of Philosophy (PhD)
Laurence C. Eisenlohr
CD4+ T cells are critical regulators of adaptive immune responses. CD4+ T cell activation is initiated and shaped by CD4+ T cell receptor (TCR) recognition of cognate peptide/major histocompatibility complex II (MHCII) complexes on the surface of antigen presenting cells (APCs). MHCII presentation of antigenic peptides has historically been viewed as a property restricted to a subset of immune cells deemed “professional” APCs – dendritic cells, macrophages, and B cells – that constitutively express MHCII. However, recently it has been demonstrated that various other immune and non-immune cell types can express MHCII, and that these “atypical” APCs make essential contributions to the regulation of CD4+ T cell responses in the periphery. In the distal lung, type II alveolar cells (AT2s), epithelial cells whose main functions are to produce surfactant and facilitate lung regeneration, have also been reported to express MHCII at homeostasis. However, the contribution of AT2 MHCII to lung adaptive immune responses, and the factors driving its expression, are unknown. Here we explore both the regulation and function of MHCII on AT2s. First, we demonstrate that AT2s constitutively express high levels of MHCII in a manner that does not require induction by inflammatory stimuli, making them unique among all other previously studied non-immune cells. Using mouse models, we also demonstrate that AT2 MHCII participates in lung immune responses in vivo. At homeostasis, aged mice lacking AT2 MHCII have lower frequencies of lung T cells with an antigen-experienced phenotype. Furthermore, following respiratory viral infection, the absence of AT2 MHCII results in increased morbidity and mortality. In both of these settings, the contribution of AT2 MHCII is moderate. Consistent with this more modest impact, we find that AT2s demonstrate a globally limited capacity to present antigen via MHCII. We propose that the combination of high MHCII expression with restrained MHCII antigen presentation enables AT2s to contribute to lung immune responses in a more measured fashion, preventing excessive inflammation that would be damaging to the delicate gas-exchange lung parenchyma.
Toulmin, Sushila, "The Regulation And Function Of Major Histocompatibility Complex Ii On Lung Type Ii Alveolar Cells" (2020). Publicly Accessible Penn Dissertations. 3990.