Neutrophils Which Migrate to Lymph Nodes Modulate CD4+ T Cell Response by a PD-L1 Dependent Mechanism

Abstract

It is well known that neutrophils are rapidly recruited to a site of injury or infection and perform a critical role in pathogen clearance and inflammation. However, they are also able to interact with and regulate innate and adaptive immune cells and some stimuli induce the migration of neutrophils to lymph nodes (LNs). Previously, we demonstrated that the immune complex (IC) generated by injecting OVA into the footpad of OVA/CFA immunized mice induced the migration of OVA+ neutrophils to draining LNs (dLNs). Here we investigate the effects of these neutrophils which reach dLNs on CD4+ T cell response. Our findings here strongly support a dual role for neutrophils in dLNs regarding CD4+ T cell response modulation. On the one hand, the CD4+ T cell population expands after the influx of OVA+ neutrophils to dLNs. These CD4+ T cells enlarge their proliferative response, activation markers and IL-17 and IFN-γ cytokine production. On the other hand, these neutrophils also restrict CD4+ T cell expansion. The neutrophils in the dLNs upregulate PD-L1 molecules and are capable of suppressing CD4+ T cell proliferation. These results indicate that neutrophils migration to dLNs have an important role in the homeostasis of adaptive immunity. This report describes for the first time that the influx of neutrophils to dLNs dependent on IC presence improves CD4+ T cell response, at the same time controlling CD4+ T cell proliferation through a PD-L1 dependent mechanism.

Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment

“…ARG1 + neutrophils in sepsis patients were shown to deplete arginine and constrain T cell function in septic shock ( Darcy et al., 2014 ) and were predictive of the development of nosocomial infections ( Uhel et al., 2017 ). Mature CD274 (PD-L1) + neutrophils (cluster 0) have been attributed suppressive functions in various conditions including HIV-1 infection ( Bowers et al., 2014 ), cancer ( Chun et al., 2015 ) and in lymph nodes ( Castell et al., 2019 ), spleen ( Langereis et al., 2017 ), and blood after LPS exposure ( de Kleijn et al., 2013 ). ARG1 + cells were mainly immature neutrophils (clusters 3–6) and did not overlap with CD274 (PD-L1) expressing cells, indicating different populations of dysfunctional and potentially suppressive neutrophils in severe COVID-19.…”

“…Single-cell transcriptomics of whole blood samples revealed mature activated neutrophils in both mild and severe COVID-19 ( Figure 7 B, cluster 2), however, expression of CD274 (PD-L1) was only found in severe COVID-19 (cluster 1), and it increased in later stages of the disease. Expression of PD-L1 on neutrophils has been associated with T cell suppression ( Bowers et al., 2014 ; Castell et al., 2019 ; de Kleijn et al., 2013 ; Langereis et al., 2017 ), suggesting that neutrophils in severe COVID-19 might exert suppressive functions. Furthermore, the expression of CD177 on mature activated neutrophils and the identification of genes associated with anti-inflammatory functions ( CD274 and ZC3H12A ) suggest a model in which neutrophils emerging prematurely from the bone marrow are programmed toward an anti-inflammatory or even suppressive phenotype in severe COVID-19.…”

“…Indeed, in future studies it will be interesting to dissect whether the myeloid subsets in COVID-19 are anti-inflammatory or even capable of suppressing other immune cells, and which pathways might be mainly involved. Clearly, PD-L1 is a prime candidate ( Bowers et al., 2014 ; Castell et al., 2019 ; de Kleijn et al., 2013 ; Langereis et al., 2017 ).…”

Quaternary Ammonium Compound Disinfectants Reduce Lupus-Associated Splenomegaly by Targeting Neutrophil Migration and T-Cell Fate

“…Neutrophils can either mitigate or accelerate SLE pathogenesis (37,38). Pro-inflammatory neutrophils exhibit part of their pathogenic roles in SLE by infiltrating the lymphoid organs to prime pathogenic T cells (41,42). However, with SLE progression, neutrophils also upregulate their expression of PD-L1, a programmed death ligand (57).…”

Oral Neutrophils: Underestimated Players in Oral Cancer

“…Neutrophils are important players in cancer immunology and their in-depth investigation helps to better understand tumor immune escape mechanisms as well as to establish more suitable biomarkers for cancer diagnostics and therapy. Neutrophils are known to contribute to cancer progression or regression via multiple mechanisms, including the suppression of cytotoxic ( 5 ) as well as helper ( 6 ) T cell responses and the stimulation of tumor angiogenesis ( 7 , 8 ). Moreover, neutrophils participate in cancer metastasis via formation of premetastatic niche in target organs ( 9 , 10 ) or via NET-mediated trapping of circulating cancer cells ( 11 ).…”