key: cord-0049042-6i0e2zkd authors: Hu, Wan-Chung title: A Framework of All Discovered Immunological Pathways and Their Roles for Four Specific Types of Pathogens and Hypersensitivities date: 2020-08-07 journal: Front Immunol DOI: 10.3389/fimmu.2020.01992 sha: aa774cd8444bb3e3792739a309a6765427c419dd doc_id: 49042 cord_uid: 6i0e2zkd nan Follicular helper T cells (Tfh) are considered as the key helper cells for B-cell germinal centers in lymph nodes and are characterized as IL-21-producing T cells (8) . Follicular dendritic cells (CD14+) are antigen presenting cells (9) , whereas lymphoid tissue inducer cells (LTi) are the innate lymphoid cells for Tfh (10) . BCL6 is a key transcription factor in Tfh development (11) . TGF-β induced by a STAT5 signal can constrain the differentiation of IL-21-producing helper T cells (12) . IL-21 production is related to STAT1and STAT3 activation. IL-21 production is also related to STAT5 activation because immunosuppressive prolactin can cause STAT5a to suppress BCL6 expression (13) . In contrast, STAT5b can upregulate BCL6 (14) . STAT5a and STAT5b have distinct target genes in immune responses (15) , and STAT5b is the transcription factor that induces Tfh. Tfh can induce B-cells to produce IgM antibodies and IL-21 produced by Tfh facilitates B cell isotype switching to IgG (16, 17) . Besides the protein antigen recognized by B cells and T cells, natural killer T (NKT) cells also recognize lipid antigens. The subtype iNKTfh plays a role in Tfh responses (18) . Thus, T lymphocytes are the first to initiate adaptive host immunity (19) (20) (21) , wherein different STAT proteins regulate different immunological pathways. If the infection tends to be eradicable, then the host immunological pathways mentioned in the following sections are generated along with other cytokines. TH1 immune responses are driven by IL-12 and are induced against intracellular bacteria or protozoa (22) . Type 2 myeloid dendritic cells (CD141+ mDC2) are the antigen presenting cells Eradicable immune responses include TH1, TH2, TH17, and THαβ. Tolerable immune responses include TH1-like (Th1L), TH9, TH22, in the TH1 response (9) . The main TH1 effector cells are stimulatory macrophages (M1), IFN-γ-secreting cytotoxic CD8 T cells (CD28+ Tc1), IFN-γ-secreting CD4 T cells, iNKT1 cells, and IgG3 -producing B-cells (23, 24) . Initiation of eradicable immunity also requires innate lymphoid cells to produce the initial cytokines that drive different immunological pathways. For TH1 immune responses, the key innate lymphoid cells are ILC1 (25) . STAT4 is the key transcription factor for TH1 immunity but T-bet also plays a vital role. TH1 responses against self-antigens present as type 4 delayed-type hypersensitivity, such as type 1 diabetes mellitus or Crohn's disease (26) . TH2 immune responses are driven by IL-4 and is induced against extracellular parasites (helminths) (27) . The antigen presenting cells in TH2 immune responses are Langerhans cells (CD1a+) (9, 28) . The main TH2 effector cells are eosinophils (iEOS), basophils/pro-inflammatory mast cells (MCt, mast cell tryptase), IL-4-/IL-5-secreting CD4 T cells, iNKT2 cells, ILC2, and IgG4/IgE-producing B-cells (29) . IgG4 activates eosinophils, and IgE activates mast cells, as in acute anaphylaxis (30) . IgG4eosinophils function to activate eosinophil-mediated cellular immunity against parasites or insects, whereas IgE-mast cells act to expel helminths or insects through a physiological mechanism. Mast cells activated by IgE can release histamine, which causes bronchoconstriction, vomiting/nausea, rhinorrhea, skin itching, gastric acidification, increased local vascular permeability, or increased bowel movement. These actions can all help to physiologically expel helminths or insects. The key transcription factor in TH2 response is STAT6 and GATA3 also plays a vital role in the TH2 immunological pathway. TH2 responses against selfantigens present as type 1 immediate allergy, such as food/drug allergy, anaphylaxis, or urticarial (31) . THαβ is distinct from traditional TH1 immune responses (2) . THαβ cells are induced against viruses and were previously called as Tr1 cells (4, 32) . THαβ immune responses are driven by IFNα/β or IL-10. The antigen presenting cells for THαβ responses are plasmacytoid dendritic cells (pDC) (9) . The main effector cells of THαβ immune responses are IL-10-producing stimulatory NK cells (CD56-CD16 + NK1 cells), IL-10/IL-27-secreting CD4 T cells, IL-10-secreting cytotoxic CD8 T cells (CD28+ Tc2), iNKT10 cells, ILC10, and IgG1-producing Bcells (23, (33) (34) (35) . The CD27 molecule is important for antiviral immunity. The key transcription factors for THαβ response are STAT1 and STAT2 (36). THαβ immune responses against self-antigens present as type 2 antibody-dependent cytotoxic hypersensitivity, such as the acute stage of myasthenia gravis or Graves' disease (37) . IL-10 is not merely an immunosuppressive cytokine; it can also have potent stimulatory effects on NK cells, cytotoxic T lymphocytes (CTLs), and B-cells. TH22 responses are part of the host innate immunity against extracellular bacteria and fungi (38) . TH22 response is driven by IL-6 or TNFα (39) . The antigen presenting cells in TH22 immune responses are type 1 myeloid dendritic cells (CD1c+ mDC1) (9) . The main TH22 effector cells are neutrophils (N1), IL-22-secreting CD4 T cells, iNKT17 cells, ILC3(NCR+), and IgG2-producing B-cells (6, 40) . The key TH22 transcription factor is STAT3; AP1 and CEBP are also important transcription factors. TGF-β can suppress IL-22 to skew the TH22 immune response toward TH17 (41) . TH22 responses against selfantigens present as type 3 immune-complex and complementmediated hypersensitivity, such as the Arthus reaction or rheumatoid arthritis (42) . The host immunological pathways induced are mainly decided by the extracellular or intracellular location of protozoa or fungi. Four IgG subtypes fit the four types of acute immunological pathways. Murine IgG antibodies also have four subclasses and are correlated with human IgG subtypes as follows: Human IgG1<->Murine IgG2a; Human IgG2<->Murine IgG3; Human IgG3<->Murine IgG2b; and Human IgG4<->Murine IgG1 (43) . hIgG1/mIgG2a function against viral antigens; hIgG2/mIgG3 function against bacterial antigen, especially polysaccharides; hIgG3/mIgG2b act against intracellular bacteria; and hIgG4/mIgG1 act against parasite antigens (44) (45) (46) . Notably, the immune response against fungi or protozoa is mainly based on their intracellular or extracellular location. Extracellular fungi such as Candida spp or Aspergillus spp usually trigger TH22 immune responses, whereas intracellular fungi such as Histoplasma spp. trigger TH1 responses. Tregs are the host immune inhibitory cells (47) driven by IL-2 and TGF-β. Regulatory dendritic cells (DCreg) are the antigen presenting cells for Tregs (48) . Regulatory innate lymphoid cells (ILCreg) are the initial helpers for Treg production (49) . The main effector cells for Tregs are the TGF-β-producing CD4 T cells, FOXP3 regulatory iNKT cells, and IgA-producing B-cells (50) . STAT5, especially STAT5a is the key transcription factor for the Treg pathway. However, both STAT5a and STAT5b play non-redundant roles in Treg generation (51) . They may first act sequentially with STAT5b activation in Tfh signaling. Combined signaling STAT5b and STAT5a induces Treg generation. The combination of Tregs and the aforementioned four immunological pathways are important to shift adaptive immunity to tolerable immunity. During initial infection, acutestage fierce cytokines can rapidly kill pathogens and infected cells or tissues. However, if the pathogen infects numerous cells in a tissue such as the liver, killing the infected cells will completely destroy the organ (52) . Thus, a regulatory T cell STAT5 signal combined with TH1/TH2/TH22/THαβ will allow the generation of CD4 T cells with less fierce inflammatory cytokines (51) . TH1like/TH9/TH17/TH3 immunological pathways are generated during chronic infection. IgA1 and IgA2 are the two types of IgA antibodies, with IgA1 being dominant in the serum, whereas IgA2 is dominant in the mucosa. TGF-β can induce IgA1 or IgA2 depending on the lymphoid follicle location (53) . In the Gutassociated lymphoid tissues (GALTs) or the Peyer's patches, IgA2 is the dominant IgA antibody produced in the gastrointestinal mucosa. In the lymph nodes at other body locations, IgA1 is the dominant IgA antibody produced. However, IgA1 is specifically related to viral protein antigens, whereas IgA2 is especially related to bacterial antigens such as LPS. The heavy-chain locus sequence of B-cell antibodies on the human chromosome 14 is IgM, IgD, IgG3, IgG1, IgA1, IgG2, IgG4, IgE, and IgA2. B-cells co-express IgM and IgD. IgG3, IgG1, and IgA1 comprise the first group for cellular immunity, whereas IgG2, IgG4, IgE, and IgA2 can be considered as the second group for humoral immunity. The gene sequence order is important as it affects the time sequence of the isotype switch. TH1-like cells (non-classic TH1) are initiated by TGF-β (STAT5 signaling) and IFN-γ (STAT4 signaling). TH1-like cells with Foxp3+ regulatory characteristics have been identified (7) . TH1 helper cells and TH1-like cells are closely related (54) . TH1-like cells are induced in chronic TH1 immune responses. Thus, these cells may be related to chronic inflammation such as long-term tuberculosis or leishmania infection (55) . The effector cells of TH1-like immune responses include suppressive macrophages (M2), ILC1, suppressive CD8 T cells (CD28-CD8+Treg), IgA1producing B-cells, iNKT1 cells, and IFN-γ-/TGF-β-producing CD4 T cells (24, 40, 56) . The TH1-like response induces type 4 delayed-type hypersensitivity, such as Crohn's disease (26) . TH9 cells are driven by IL-4 (STAT6 signaling) combined with TGF-β (STAT5 signaling) (57) (58) (59) . Thus, TH9 cells are closely related to the TH2 immunological pathway in parasite immunity (60) . The cells are characterized as IL-9-secreting CD4 T cell. TH9 cells are important under a chronic allergic condition such as asthma. Thus, TH9 helper cells are chronic T helper cells related to TH2 immune response. The effector cells of TH9 immunity include regulatory eosinophils, basophils/profibrotic mast cells (MCct, mast cell chymase, and tryptase), ILC2, IL-9-producing CD4 T cells, iNKT2 cells, and IgA2-producing B-cells (40, 61) . TH9 immune responses present as type 1 allergy, including asthma (29) . TH17 cells are driven by IL-6/IL-1 combined with TGF-β (5). Thus, TH17 cells are closely related to the TH22 immunological pathway against extracellular bacteria and fungi (62) . TH17 cells are characterized as IL-17-secreting CD4 T cells. TH17 cells are important in chronic immune-complex-mediated diseases such as rheumatic arthritis. The TH17 helper cell is the chronic T helper cell related to TH22 immunity. TGF-β with STAT5 can suppress the acute IL-22-producing cells and enhance the chronic IL-17-producing cells (41) . Owing to the role of TGFβ in TH17 immunity, regulatory IL-17-producing cells have been noted. The effector cells of TH17 immunity include regulatory neutrophils (N2), ILC3(NCR-), IL-17-producing CD4 T cells, iNKT17 cells, and IgA2-producing B-cells (40, 63) . TH17 immunity presents as type 3 immune-complex hypersensitivity, including ulcerative colitis or rheumatoid arthritis (42) . TH3 cells are driven by IL-10 and TGF-β (64, 65) . Thus, TH3 cells are closely related to the THαβ immunological pathway against viruses (66) . These cells also produce IL-10 and TGF-β. Thus, TH3 helper cells are important for chronic antibody-dependent cellular cytotoxic hypersensitivity. TH3 cells are the chronic helper T cells corresponding to THαβ helper cells. The TH3 immune effector cells include IL-13-producing regulatory NK cells (CD56 + CD16-NK2 cells), ILC10, IL-10-and TGF-β-secreting CD4 T cells, suppressive CD8 T cells (CD28-CD8+ Treg), iNKT10 cells, and IgA1-producing B-cells (34, 35, 56, 67, 68) . IgA1 of TH3 immune responses is produced in the serum and acts against viral protein antigens. TH3 immune responses induce type 2 antibody-dependent cytotoxic hypersensitivity, including the chronic stage of Systemic Lupus Erythematosus (SLE) (69) . The summary diagram includes complete picture of the 4 × 2 + 2 immunological pathways ( Table 1). The TH1, TH2, TH22, and THαβ eradicable immune responses correspond with the TH1-like, TH9, TH17, and TH3 tolerable The author is thankful for the instructions provided by Professors Alan Scott, Louis August Bourgeois, and Pien-Chien Huang during his Ph.D. study in the Department of International Health, Johns Hopkins University, Bloomberg School of Public Health. The author is also grateful for the guidance from Professors Chi-Huey Wong and Alice Lin-Tsing Yu in his postdoctoral research at the Genomics Research Center of Academia Sinica, Taiwan. This manuscript has been released as a pre-print at BioRxiv (70) . Two types of murine helper T cell clone. I. 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