Antigen presentation by lung epithelial cells directs CD4+ TRM cell function and regulates barrier immunity

Abstract

Barrier tissues are populated by functionally plastic CD4+ resident memory T (TRM) cells. Whether the barrier epithelium regulates CD4+ TRM cell locations, plasticity and activities remains unclear. Here we report that lung epithelial cells, including distinct surfactant protein C (SPC)lowMHChigh epithelial cells, function as anatomically-segregated and temporally-dynamic antigen presenting cells. In vivo ablation of lung epithelial MHC-II results in altered localization of CD4+ TRM cells. Recurrent encounters with cognate antigen in the absence of epithelial MHC-II leads CD4+ TRM cells to co-express several classically antagonistic lineage-defining transcription factors, changes their cytokine profiles, and results in dysregulated barrier immunity. In addition, lung epithelial MHC-II is needed for surface expression of PD-L1, which engages its ligand PD-1 to constrain lung CD4+ TRM cell phenotypes. Thus, we establish epithelial antigen presentation as a critical regulator of CD4+ TRM cell function and identify epithelial-CD4+ TRM cell immune interactions as core elements of barrier immunity.

Recruitment and training of alveolar macrophages after pneumococcal pneumonia

“…Naturally acquired immune defense against pneumococcal pneumonia can be achieved in mice by administering two self-limiting respiratory infections with Streptococcus pneumoniae serotype 19F (Sp19F) spaced one week apart followed by a month of recovery, after which the mice demonstrate a long-lasting heterotypic (serotype-mismatched) protection that involves remodeled AM of unknown sources (21,(23)(24)(25)(26). To determine whether and how AM numbers change during the infection history that establishes heterotypic protection against pneumococcal pneumonia (21,(23)(24)(25)(26), naïve mice were ushered through serial infections and at designated time-points lungs were collected and digested to single cell suspensions for flow cytometry.…”

“…The AM remodeling induced by adenoviral infections, including increased MHC-II, depends on T cell-derived IFNg (22). Pneumococcal-experienced lungs exhibit a transient recruitment of effector CD4+ T cells that become a population of resident memory CD4+ T cells, and these CD4+ cells express IFNg, IL-17, and other cytokines (23)(24)(25)(26). To test whether CD4+ T cells are essential for the remodeled phenotype of AM in pneumococcus-experienced lungs, mice received doses of GK1.5 antibodies to deplete CD4+ cells (or isotype-matched non-specific IgG as control) throughout the initial infections, and then lungs were characterized at day 35.…”

“…In contrast, surface MHC-II of AM from experienced IFNg-/-mice was significantly less than in WT counterparts, and not different from naïve mice without a pneumococcal infection history (Figure 5C), indicating a requirement for IFNg for this outcome. Since CD4+ TRM cells are another critical component of immunity in lungs with pneumococcal experience (23)(24)(25), we investigated whether loss of IFNg would impact numbers of these cells. Like AM Siglec F but contrasting with AM MHC-II, the CD4+ TRM cell numbers were unaffected by deficiency of IFNg (Figure 5D).…”

“…Recovery from pneumococcal pneumonia results in a profoundly improved protection against heterotypic infection (i.e., by a different serotype), due to a combination of resident memory lymphocytes as well as the remodeling of AM (21,(23)(24)(25)(26). The remodeled AM in this setting have increased surface MHC-II, decreased surface Siglec F, enhanced creatine metabolism, and profoundly altered transcriptomes both at rest and in response to infection, better matching the immune responses of human AM (21).…”

C-X-C Motif Chemokine Ligand 9 and Its CXCR3 Receptor Are the Salt and Pepper for T Cells Trafficking in a Mouse Model of Gaucher Disease

“…Two major groups T cells are termed CD4 + T-helper and CD8 + T cytotoxic cells [ 28 ]. CD4 + T helper cells showed significant heterogeneity of their cytokine expression profiles that lead to the discoveries of interferon gamma (IFNγ) producing T helper 1 (Th1), interleukin (IL) 4 producing Th2, and IL17 producing Th17 cell subsets [ 26 , 29 , 30 ]. This cytokine heterogeneity specifies the interaction of T cells with other immune cells and thereby their function in host defense and inflammation [ 25 , 31 , 32 , 33 , 34 , 35 , 36 ].…”