How Neutrophils Shape Adaptive Immune Responses

Abstract

Neutrophils are classically considered as cells pivotal for the first line of defense against invading pathogens. In recent years, evidence has accumulated that they are also important in the orchestration of adaptive immunity. Neutrophils rapidly migrate in high numbers to sites of inflammation (e.g., infection, tissue damage, and cancer) and are subsequently able to migrate to draining lymph nodes (LNs). Both at the site of inflammation as well as in the LNs, neutrophils can engage with lymphocytes and antigen-presenting cells. This crosstalk occurs either directly via cell-cell contact or via mediators, such as proteases, cytokines, and radical oxygen species. In this review, we will discuss the current knowledge regarding locations and mechanisms of interaction between neutrophils and lymphocytes in the context of homeostasis and various pathological conditions. In addition, we will highlight the complexity of the microenvironment that is involved in the generation of suppressive or stimulatory neutrophil phenotypes.

Keywords: T-cells; immune-paralysis; immune-regulation; inflammation; myeloid-derived suppressor cells; neutrophil; neutrophil phenotypes.

Figure 1

Localization of interaction between neutrophils and lymphocytes at sites of inflammation and in lymphoid tissue. Invasion of pathogens or inflammation due to necrosis and cancer leads to extravasation of neutrophils. (1) Interaction of neutrophils with T-cells in the peripheral tissue. (2) MAC-1 and CXCR4-dependent migration of neutrophils to LNs via afferent lymphatics during inflammation (22). (3) IL17 and CCL21-mediated migration of neutrophils via HEVs to the LN that requires MAC-1, LFA-1, and l-selectin (19, 20). (4) Inhibition of humoral responses by neutrophils in the IFZ and medullar region (23). HEV, high endothelial venule; FZ, follicular zone; IFZ, interfollicular zone.

Figure 2

Mechanisms involved in T-cell inhibition (left panel) and activation (right panel) by neutrophils. Neutrophils can establish T-cell inhibition by (1) degranulation of granular constituents. The serine proteases elastase and cathepsin G inactivate T-cell stimulating cytokines, IL-2 and IL-6, and catalyze shedding of cytokine receptors for IL-2 and IL-6 on T-cells (72, 73). (2) Production of ROS and release of arginase. Both agents can result in downregulation of TCRζ on T-cells, thereby arresting the cell in the G0-G1 phase (, –78). (3) Expression of PD-L1. Upregulation of this ligand is associated with interferon-dependent PD1-mediated T-cell apoptosis (35, 56). T-cell activation by neutrophils is attained by (4) indirect antigen presentation. Dendritic cells take up antigens from apoptotic neutrophils and serve as APC for T-cells (61). (5) Direct antigen presentation. Neutrophils posses the capacity to cross-prime CD8⁺ T-cells directly in a MHCI-dependent manner (32). (6) Release of microbial metabolites (HMB-PP). Neutrophils release bacterial products after ingestion to activate γδ-T-cells (42).