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Review
. 2018 Jul 31;11(1):97.
doi: 10.1186/s13045-018-0637-x.

Immune cell subset differentiation and tissue inflammation

Pu Fang  1 , Xinyuan Li  2 , Jin Dai  1 , Lauren Cole  1 , Javier Andres Camacho  1 , Yuling Zhang  3 , Yong Ji  4 , Jingfeng Wang  3 , Xiao-Feng Yang  1   5 , Hong Wang  6   7
Affiliations
Review

Immune cell subset differentiation and tissue inflammation

Pu Fang et al. J Hematol Oncol. .

Abstract

Immune cells were traditionally considered as major pro-inflammatory contributors. Recent advances in molecular immunology prove that immune cell lineages are composed of different subsets capable of a vast array of specialized functions. These immune cell subsets share distinct duties in regulating innate and adaptive immune functions and contribute to both immune activation and immune suppression responses in peripheral tissue. Here, we summarized current understanding of the different subsets of major immune cells, including T cells, B cells, dendritic cells, monocytes, and macrophages. We highlighted molecular characterization, frequency, and tissue distribution of these immune cell subsets in human and mice. In addition, we described specific cytokine production, molecular signaling, biological functions, and tissue population changes of these immune cell subsets in both cardiovascular diseases and cancers. Finally, we presented a working model of the differentiation of inflammatory mononuclear cells, their interaction with endothelial cells, and their contribution to tissue inflammation. In summary, this review offers an updated and comprehensive guideline for immune cell development and subset differentiation, including subset characterization, signaling, modulation, and disease associations. We propose that immune cell subset differentiation and its complex interaction within the internal biological milieu compose a "pathophysiological network," an interactive cross-talking complex, which plays a critical role in the development of inflammatory diseases and cancers.

Keywords: B cell; Cancer; Cardiovascular disease; Dendritic cell; Immune cell subset differentiation; Macrophage; Monocyte; T cell.

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Figures

Fig. 1
Fig. 1
General processes of hematopoietic stem cell differentiation. Long-term hematopoietic stem cells (LT-HSC) differentiate into common lymphoid progenitors (CLP) and common myeloid progenitors (CMP). CLP are committed to lymphoid genesis and differentiate into B cells (BC), T cells (TC), and natural killer T cells (NKT) (1). CMP are committed to megaerythroid genesis and could differentiate into erythrocytes and platelets (2). CMP could also differentiate into granulocyte-macrophage progenitors (GMP), and then differentiate into granulocytes (neutrophils (NØ), eosinophils, basophils, and mast cells) and “NØ-like” MC. In addition, CMP could differentiate into monocyte-dendritic progenitors (MDP), which are committed to myeloid genesis and differentiate into common dendritic cell progenitor (CDP)-derived plasmocytoid dendritic cells (pDC) and common monocyte precursor (cMoP)-derived monocytes (MC), which further differentiate into monocyte-derived DC (mDC) and macrophages (MØ) (3)
Fig. 2
Fig. 2
Lymphoid genesis and subset differentiation. a Differentiation of T cells (TC). Common lymphoid progenitors (CLP) migrate from bone marrow (BM) to thymus entering double-negative (DN, CD4-CD8-) stage (1). These cells initially express adhesion molecule CD44 and then α-chain of the interleukin (IL)-2 receptor (CD25), eventually lose CD44 and maintain CD25, rearrange T cell receptor (TCR) β chain, and then enter double-positive (DP, CD4+CD8+) stage (2), a transition stage of TC maturation. The DP TC then lose their membrane expression of CD25, rearrange their α chain, generate a complete αβ TCR, which has the capacity to recognize host major histocompatibility complex (MHC) molecules (positive selection), therefore survives and enters single positive (SP, CD4+, or CD8+) stage (3). After TC bind to MHCI, they become CD8+ TC and are termed as cytotoxic TC (Tc), whereas those binding to self-peptide–MHCII become CD4+ TC and are called as Naïve TC (T0). These SP TC then undergo “negative selection” to eliminate those that recognize MHC that bound to self-peptides, thereby completing the process of TC maturation. T0 cells can differentiate into effector TC (T helper cells Th1, Th2, Th17) and regulatory T cells (Treg) under the regulation of antigen (Ag) presentation, immune checkpoint, cytokine inducers, and metabolite-associated danger signal (MADS), and produce functional cytokines. b Differentiation of B cells (BC). In BM, B1/B2-specific CLP first differentiate into B1/B2 progenitor BC (pro-BC), B1/B2 precursor BC (pre-BC) with assembled pre-B cell receptor (BCR) and then became immature B1/B2 BC that express BCR and secrete IgM. Immature B1/B2 BC then migrate to spleen and differentiate into follicular (Fo) B2 BC, marginal zone (MZ) B2 BC, or mature B1 BCs, depending on the transcription factors that are induced by different signals. Fo BC can generate GC BC with follicular DC (a stromal cell) retained-Ag encounter and Tfh help. An affinity-matured Ab response then produce durable memory BC with high affinity to foreign Ag, as well as long lived plasma cells, which can secrete large quantities of Ab. B2 BC constitute the majority of splenic BCs. Mature B1 BC further differentiate into B1a secreting IgM and IL-10, and B1b producing IgM
Fig. 3
Fig. 3
Myeloid genesis and subset differentiation. a Differentiation of dendritic cells (DC). Monocyte-dendritic progenitors (MDP) are the direct precursors to common dendritic cell progenitors (CDP) and monocytes (MC), which both give rise to DC lineages. In bone marrow (BM), CDP become precursor DC (pre-DC) and differentiate into immature plasmocytoid DC (pDC) and mature pDCs, and then exit the BM traveling through the blood to secondary lymphoid organs and non-hematopoietic tissues. In the lymphoid or non-lymphoid tissues, pre-DC become CD103+ classical/conventional DC (cDC) through transitional pre-cDC stage and CD11b+ cDC directly. In cultured system, MC differentiate into immature monocyte-derived DC (mDC) in the presence of interleukin (IL)-4 and granulocyte macrophage colony-stimulating factor (GM-CSF). Terminal differentiated mDC are induced upon stimulation with inflammatory cytokines (IL-1, IL-6, and tumor necrosis factor (TNF)) and prostaglandin E2 (PGE2). b Differentiation of monocytes (MC)/macrophages (MØ) in human. In the steady state, human classical MC can differentiate into intermediate MC, then patrolling non-classical MC. Classical MC have a high antimicrobial capability due to their potent capacity of phagocytosis. Intermediate MC secrete inflammatory cytokines and have inflammatory properties, whereas non-classical MC mainly patrol along endothelium. During inflammation, all the MC subsets are tethered and penetrate vessel wall and then mature into anti-inflammatory MØ (M2a, M2b, M2c, and Mhem) and inflammatory MØ (M1 and M4) in tissue. Classical, intermediate and non-classical MC can be further divided into CD40+ and CD40- MC subsets. CD40+ classical/intermediate MC are induced in cardiovascular disease (CVD) and further elevated with the progress of chronic kidney disease (CKD). Dashed arrows indicate potential differentiation pathways, while solid arrows indicate experimentally verified differentiation pathways
Fig. 4
Fig. 4
Representative signaling pathways of immune cell subset differentiation. a TC. b BC. c DC. d MC. e MØ
Fig. 5
Fig. 5
Molecular and cellular modulation of immune cell subsets and its impact on atherosclerosis. Immune cell subsets play different roles in atherosclerosis and can be suppressed by individual endogenous inhibitors as indicated. a Inflamed phase in immunity. Inflammatory subsets are induced by antigens (Ag), inflammatory cytokines, pathogen-associated molecular patterns (PAMP), danger-associated molecular patterns (DAMP), in inflamed phase of disease and promote atherosclerosis. b Resolution phase in immunity. Anti-inflammatory subsets are induced in resolution phase of disease and suppress atherosclerosis. There are many inhibitors can could interfere with immune cell subset functions
Fig. 6
Fig. 6
Model of differentiation of inflammatory mononuclear cell, their interaction with endothelial cells and contribution to lymphocyte subset differentiation and tissue inflammation. In early stage of atherosclerosis, Ly6Cmiddle + high monocytes (MC) transmigrate to sub-endothelial space of vessel and further differentiate to M1 macrophages (MØ) and monocyte-derived dendritic cells (mDC). mDC activate T helper cells Th1, Th17, and B2 cells, resulting in chronic inflammation in atherosclerotic plaque. All of these inflammatory mononuclear cell subsets promote atherosclerosis development partially through production of proinflammatory cytokines
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