Neutrophils have long been recognised as professional killers. Eradication of bacteria and fungi was thought to be their main task. Evidence is, however, accumulating that apart from their direct anti-microbial function, neutrophils participate in subsequent modulation of (adaptive) immune responses in severe inflammation [
89‐
91]. Under these inflammatory conditions, neutrophils produce chemokines and secrete granule contents which can subsequently attract and modulate the function(s) of T cells both directly and indirectly [
92,
93]. For instance, neutrophil elastase reduces expression of co-stimulatory molecules by dendritic cells, limiting maturation and induction of a proper Th1 response [
94]. In addition, T cells in the inflammatory microenvironment may be affected by neutrophil elastase by cleavage of their IL-2 and IL-6 receptors (Fig.
1a) [
95]. Another mechanism of immune-modulation was observed in macrophages after phagocytosis of apoptotic neutrophils. Under these conditions immune responses of macrophages shift towards a more anti-inflammatory cytokine profile [
96]. Furthermore, neutrophils themselves have been shown to produce anti-inflammatory cytokines such as IL-1ra and IL-10 [
97]. However, the evidence regarding IL-10 production by neutrophils is controversial, as it has only been shown in mice with mycobacterial infections [
98]. In humans neutrophils are unable to produce IL-10 [
99]. Direct regulation of T-cell responses by neutrophils is slowly becoming an established concept. A large body of evidence demonstrates that a heterogeneous group of immature mononuclear cells and neutrophils termed myeloid-derived suppressor cells (MDSCs) can suppress T-cell responses in several murine tumour models. In addition, these cells have been shown to play a role in various models of infectious diseases, organ transplantation and autoimmune diseases [
100]. Identification of human immature granulocytic MDSCs has proven to be challenging though. In particular, their differentiation from mature neutrophil phenotypes seen in the blood during acute inflammation remains to be established, as we have reviewed in detail elsewhere [
101]. The mechanisms by which MDSCs can suppress T cells include the expression and secretion of arginase-1, which depletes arginine from the microenvironment (Fig.
2) [
102]. Depletion of L-arginine, which is an essential amino acid, results in cell cycle arrest of T cells in the G0–G1 phase [
103]. Furthermore, in human inflammation we and others have observed a population of mature CD62L
dim neutrophils capable of suppressing T-cell responses through a mechanism which relies on ROS release in an immunological synapse [
104]. Recently, similar neutrophils in septic shock patients have been found to express arginase-1 and suppress T-cell functions [
105]. Another mechanism by which neutrophils might inhibit T-cell responses is through PD-L1 [
106]. Neutrophils isolated from sepsis patients express the surface protein PD-L1, a potent inducer of apoptosis in T cells. The underlying mechanism of PD-L1 expression is an interferon-gamma-dependent process [
106]. The PD-1–PD-L1 axis is thought to be an important mechanism in immune suppression in septic patients by inducing lymphocyte apoptosis and monocyte dysfunction [
107]. Blocking this axis after the induction of sepsis by administering a PD-1-blocking antibody improved survival in mice [
108]. This suppressive mechanism might be protective in tissues with severe inflammatory infiltrates. On the other hand, this process might be unwanted when neutrophils migrate to lymph nodes and engage with adaptive immunity, as has been described under various conditions [
109]. In these lymph nodes neutrophils are able to inhibit humoral immune responses through interaction with T and B lymphocytes [
109,
110].