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Review
. 2021 Nov 22:12:755856.
doi: 10.3389/fimmu.2021.755856. eCollection 2021.

Reactive Oxygen Species: Do They Play a Role in Adaptive Immunity?

Esen Yonca Bassoy  1   2 , Michael Walch  3 , Denis Martinvalet  4   5
Affiliations
Review

Reactive Oxygen Species: Do They Play a Role in Adaptive Immunity?

Esen Yonca Bassoy et al. Front Immunol. .

Abstract

The immune system protects the host from a plethora of microorganisms and toxins through its unique ability to distinguish self from non-self. To perform this delicate but essential task, the immune system relies on two lines of defense. The innate immune system, which is by nature fast acting, represents the first line of defense. It involves anatomical barriers, physiological factors as well as a subset of haematopoietically-derived cells generically call leukocytes. Activation of the innate immune response leads to a state of inflammation that serves to both warn about and combat the ongoing infection and delivers the antigenic information of the invading pathogens to initiate the slower but highly potent and specific second line of defense, the adaptive immune system. The adaptive immune response calls on T lymphocytes as well as the B lymphocytes essential for the elimination of pathogens and the establishment of the immunological memory. Reactive oxygen species (ROS) have been implicated in many aspects of the immune responses to pathogens, mostly in innate immune functions, such as the respiratory burst and inflammasome activation. Here in this mini review, we focus on the role of ROS in adaptive immunity. We examine how ROS contribute to T-cell biology and discuss whether this activity can be extrapolated to B cells.

Keywords: B lymphocytes; T lymphocytes; adaptive immunity; reactive oxygen species; tumor microenvironment.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Endogenous ROS contribute to T and B cell receptor signaling. The engagement of the B-cell receptor (BCR) or T-cell receptor (TCR) and their respective co-receptors CD28 and CD19/CD21 triggers intracellular phosphorylation signaling cascades resulting in the activation of transcription factors AP1, NF-κB, NFAT, OCA-B/OBF-1 IRF-4, which are critical for T and B lymphocyte activation. In T cell, dark grey, TCR/CD28 stimulation induces the phosphorylation and activation of the kinases p56lck (LCK) and ZAP-70, the phospholipase Cg (PLCg). CD28 recruits growth factor receptor bound protein 2 (Grb2), which docks the complex formed by SH2 domain containing leukocyte protein of 76kDa (SLP-76)/Linker for activation of T-cells (LAT)/signal transducer protein Vav1. The latter complex recruitment closer to the membrane facilitating its activation by ZAP70. PLCg generates inositol 3 phosphate (IP3) to mobilize intracellular Ca2+ stores resultingin the activation of the phosphatase calcineurin. PLCg also generates diacylglycerol (DAC) to activate protein kinase C (PKC), c-Jun N-terminal Kinase (JNK) and mitogen-activated protein kinase/extracellular signal-regulated kinases (MEK/ERK) cascade. Calcineurin dephosphorylates nuclear factor of activated T cells (NFAT), allowing its nuclear translocation. PKC allows NF-κB nuclear translocation by removing of the inhibitor (IkB), while JNK and ERK activate AP1. In B cells, light grey, BCR/CD19/CD21 stimulation initiates a phosphorylation cascade starting with the activation of the kinases Lyn and SYK, leading to the activation of B cell linker protein (BLNK), B Cell adaptor molecule for phosphoinositide 3-Kinase (PI3K) (BCAP) and PLCg, ultimately resulting in PKC, JNK and ERK activation. Both TCR and BCR signaling potentiate mitochondrial respiration and activate metabolic pathways through their action on the complex formed by PI3K, protein kinase B (PKB/AKT) and mammalian target of rapamycin (mTOR). These signaling cascades are potentiated by ROS (H2O2 and O2-.) from NADPH oxidases (NOX/DUAOX) and from the mitochondria (red arrows). In some instances, NOX triggers the oxidative modification of ZAP70 and LCK to precipitate their degradation and blunt activation (dashed bloc red line).
Figure 2
Figure 2
Exogenous ROS modulate lymphocyte effector functions and viability. At low doses of microenvironmental ROS, both B and T lymphocytes have normal effector function (smiley face lymphocytes). Exposure to mild doses of exogenous ROS affects the lymphocyte effector functions (weary face lymphocytes), while acute exposure to high doses affects their viability. The threshold between mild and acute exposure strongly depends upon the lymphocyte subset and maturation status.
Figure 3
Figure 3
ROS in the tumor microenvironment. The metabolic stress imposed by the neoplastic transformation and uncontrolled proliferation combined with the hypoxic nature and marked production of ROS contribute to the chronic inflammation state of the tumor microenvironment (TME). The oxidative nature of the TME is exacerbated by its infiltration with immune cells with altered phenotypes [neutrophils, macrophages and myeloid derived suppressor cells [MDSCs)]. NK cells and CD8+ effector memory T cells are particularly sensitive to even low doses of H2O2, while the T regulatory cells are protected from H2O2-dependent inhibition of their suppressive function and H2O2-induced death. Taken together, this supports that the oxidized TME may be a particularly inhospitable site for NK cells and CD8 T cells and detrimental to T cell-based adoptive cell transfer therapies.
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