Microbial uptake in oral mucosa–draining lymph nodes leads to rapid release of cytotoxic CD8 ⁺ T cells lacking a gut-homing phenotype

Abstract

The gastrointestinal (GI) tract constitutes an essential barrier against ingested microbes, including potential pathogens. Although immune reactions are well studied in the lower GI tract, it remains unclear how adaptive immune responses are initiated during microbial challenge of the oral mucosa (OM), the primary site of microbial encounter in the upper GI tract. Here, we identify mandibular lymph nodes (mandLNs) as sentinel lymphoid organs that intercept ingested Listeria monocytogenes (Lm). Oral Lm uptake led to local activation and release of antigen-specific CD8 + T cells that constituted most of the early circulating effector T cell (T EFF ) pool. MandLN-primed T EFF disseminated to lymphoid organs, lung, and OM and contributed substantially to rapid elimination of target cells. In contrast to CD8 + T EFF generated in mesenteric LN (MLN) during intragastric infection, mandLN-primed T EFF lacked a gut-seeking phenotype, which correlated with low expression of enzymes required for gut-homing imprinting by mandLN stromal and dendritic cells. Accordingly, mandLN-primed T EFF decreased Lm burden in spleen but not MLN after intestinal infection. Our findings extend the concept of regional specialization of immune responses along the length of the GI tract, with CD8 + T EFF generated in the upper GI tract displaying homing profiles that differ from those imprinted by lymphoid tissue of the lower GI tract.

Regulator of G-protein signaling 1 critically supports CD8+ TRM cell-mediated intestinal immunity

“…We deliberately administered Lm -OVA by an intragastric gavage (i.g), rather than by oral feeding: infection with Lm-OVA via the i.g. route, favors the induction of CCR9 expressing gut homing effector CD8αβ+ T cells whereas the oral administration of Lm-OVA favors the systemic dissemination of antigen-specific T cells after their priming in the draining submandibular lymph nodes as recently demonstrated by us ( 20 ).…”

“…CD11c EYFP mice ( 18 ) or C57BL/6JRj mice received 2.5x10 5 OT-I Rgs1 +/+ -tdT + 2.5x10 5 OT-I Rgs1 -/- -GFP ( 16 ) and were orally infected with 2x10 9 Lm-OVA the day after as described ( 20 ). At day 8 and at day 30 p.i., the gut lumen was surgically exposed (kept in saline at 37°C), and 2-photon microscopy (2-PM) was performed with an Olympus BX50WI microscope and a TrimScope 2-PM system controlled by ImSpector software (LaVisionBiotec, Bielefeld, Germany).…”

Epithelial immune activation and intracellular invasion by non-typeable Haemophilus influenzae

“…Such anatomical compartmentalization of the mucosal immune system, leading to different immune responses at different sites, is becoming increasingly apparent. For instance, recent murine work has demonstrated imprinting of different T cell responses induced to Listeria monocytogenes by oral inoculation compared with gastric inoculation ( Barreto de Alburquerque et al., 2022 ). Oral inoculation primed effector T cells which disseminated to lymphoid organs, lung and oral mucosa but did not home to the gut, whilst T cells induced by gastric inoculation were gut homing.…”

Cancer immunotherapy responses persist after lymph node resection

“…Further, it is important to investigate lymphatic drainage patterns after non-skin LN dissection as ICB treatment increases survival in non-small cell lung cancer 79 and colorectal cancer 80 patients. Notably, regional specification is found in immunity generated in DLNs 81 . Therefore, after CLND, activated T cells in distant LNs may not be able to infiltrate the cancer lesion, which is dictated by anatomic location 81 .…”

“…Notably, regional specification is found in immunity generated in DLNs 81 . Therefore, after CLND, activated T cells in distant LNs may not be able to infiltrate the cancer lesion, which is dictated by anatomic location 81 . In contrast to preclinical studies, clinical trials are more statistically powered 82 .…”