Abstract
Background: Since Professor Mosmann proposed TH1 and TH2 immune reactions. Recently, more host immunological pathways are discovered including TH17, TH9, TH22, Tr1, Treg, Tfh, TH3, and THllike. These immunological pathways’ functional clinical importance is not clearly known. In this article, the host immunological pathways are re-organized to get a clear picture. Main text: There are four eradicable immune responses: TH1/TH2/TH22/THαß which are corresponding to four tolerable immune responses: TH1Like/TH9/TH17/TH3. TH1/TH1like is immunity against intracellular bacteria or protozoa and is related to type4 delayed-type hypersensitivity. TH1 immunity includes M1 macrophage, CTL(Tc1/EM4), IFNg CD4 T cell, and lgG3 B cells. THILike immunity includes M2 macrophage, suppressive CTL(EM3), IFNg/TGFβ CD4 T cell, and IgA1 B cells.TH2/TH9 is immunity against helminthes and is related to type1 immediate allergy.TH2 immunity includes eosinophils(iEOS), mast cells, IL-4 CD4 T cells, and lgE/lgG4 B cells. TH9 immunity includes eosinophils (rEOS), basophils, IL-9 CD4 T cells, and lgA2 B cells. TH22/TH17 is immunity against extracellular bacteria or fungi and is related to type3 immune-complex hypersensitivity. TH22 immunity includes neutrophils(N1), IL-22 CD4 T cells, and lgG2 B cells. TH17 immunity include neutrophils(N2), IL-17 CD4 T cells, and lgA2 B cells. THαß/TH3 is immunity against viruses and is related to type2 antibody dependent cytotoxic hypersensitivity. THαβ immunity includes stimulatory NK cells(NK1), CTL(Tc2/EM1), IL-10 CD4 T cells, and IgGl B cells. TH3 immunity includes regulatory NK cells(NK2), suppressive CTL(EM2), IL-10/TGFß CD4 T cells, and IgA1 B cells. THfh is the stimulatory pathway to initiate adaptive immunity. Cytokines can help to drive initiatory immunities to eradicable immune reactions. Another inhibitory pathway Treg is the key player to shift immune responses to tolerable immune responses for generating milder cytokines and other immune mediators to avoid severe destruction of tissue-organ during chronic large scale infection. Conclusion: This 4x2+2 is the whole diagram of host immunological pathways describing initiatory, eradicable, regulatory, and tolerable immune responses.
There are many discovered host immunological pathways including traditional TH1, TH2, TH3, TH17, TH22, THfh, Treg, TH9, and Tr1(THαß). These identified pathways are not logically organized. Here, I will propose a detailed picture about the whole context of host immunological pathways. (Figure 1)
The traditional TH1/TH2 paradigm was proposed by Dr. Mosmann in 1986.(56) TH1 was thought the host immunity against viruses and intracellular bacteria. TH2 is the host immunity against multicellular parasites (helminthes). In my PhD thesis, I proposed a new THαβ immunological pathway against viruses that is divided from traditional TH1 immunity.(36) The TH1 immunity is then focusing on intracellular bacteria and protozoa. Then, TH3 immunity and Tr1 immunological pathways were identified later.(44, 45) Recently, additional immune responses are discovered including TH17, TH22, THfh, Treg, and TH1-like immunological pathways.(13,20,22,31,35)
Main text
Initiatory immune response
Follicular helper T cells (THfh) is thought to be the key helper cells for the B cell germinal centers in lymph nodes.(84) THfh cells are characterized by IL-21 producing T cells(23, 50). BCL6 is a key transcription factor for THfh. TGF beta with STAT5 signal can constrain the differentiation of the IL-21 producing helper T cells(49, 52). IL-21 production is also related to STAT1 and STAT3 activation as well as STAT5 activation. Since immunosuppressive prolactin can induce STAT5a to suppress BCL6 expression.(40, 78) On the contrary, STAT5b can up-regulate BCL6.(74) STAT5a and STAT5b have distinct target genes in immune responses.(82) The transcription factor to induce THfh should be STAT5b. BCL6 is key in THfh development.(7, 47, 61) Follicular helper T cell can induce B cells to start to produce IgM antibody.(9) Thus, it is the earliest T lymphocytes to begin the adaptive host immunity.(12, 59, 73) Different STAT proteins regulate different immunological pathways.(51, 75) If the infection is tend to be eradicable, the following host immunological pathways are generated with other cytokines.
Eradicable immune responses
TH1 immunity is driven by IL-12. It is the host immunity against intracellular bacteria or protozoa. The main effector cells of TH1 immunity are stimulatory macrophages (M1), IFNg secreting cytotoxic CD8 T cells (EM4 CD27-CD28+ Tc1), IFNg secreting CD4 T cells, and lgG3 producing B cells.(3, 28, 38, 70) The key transcription factors for TH1 immunity is STAT4. T-bet also plays a vital role in TH1 immunological pathway. TH1 immunity against self antigen is Type 4 Delayed-type hypersensitivity such as type1 diabetes mellitus.(41, 55)
TH2 immunity is driven by IL-4. TH2 immunity is against extracellular parasites (helminthes). The main effector cells of TH2 immunity are eosinophils (iEOS), mast cells, IL-4/IL-5 secreting CD4T cells, and lgG4/lgE producing B cells.(53) lgG4 activates eosinophils and IgE activates mast cellssuch as in acute anaphylaxis, respectively.(72) The key transcription factor for TH2 immunity is STAT6. GATA3 also plays a vital role in TH2 immunological pathway. TH2 immunity against self antigen is Type1 immediate allergy such as food/drug allergy or urticaria.(34)
THαβ is distinguished from the traditional TH1 immunity(36). THαβ immunity is against viruses. It was called Tr1 cell by some previous researchers.(45) THαßimmunity is driven by IFNa/b or IL-10. The main effector cells of THαβ immunity are IL-10 producing stimulatory NK cells(CD56-CD16+ NK1 cells), IL-10/1L-27 secreting CD4 T cells, IL-10 secreting cytotoxic CD8 T cells (EMI CD27+CD28+Tc2), and IgGl producing B cells.(15,38,41,67,70) CD27 molecule is important for virus immunity.(33, 58) The key transcription factor for THαβ immunity is STATland STAT2.(60) THαß immunity against self antigen is Type 2 Antibody dependent cytotoxic hypersensitivity such as acute stage of Myasthenia Gravis. It is worth noting that IL-10 is not merely a immunosuppressive cytokine; it can have potent stimulatory effects on NK cells, CTLs, and B cells.(57)
TH22 is the host innate immunity against extracellular bacteria and fungi(2, 87). TH22 is driven by IL-6 or TNFa(26, 79). The main effector cells for TH22 immunity are PMNs(N1), IL-22 secreting CD4 T cells, complements, pentraxins, and lgG2 producing B cells.(21, 22) The key transcription factor for TH22 is STAT3(89). AP1 and CEBP are also important. TGF beta can suppress IL-22 to skew to TH17 immunity.(71) TH22 against self antigen is Type 3 immune-complex and complement mediated hypersensitivity such as Arthus reaction.(91)
It is interesting to know that four IgG subtypes fit the four types of acute immunological pathways. Murine IgG antibodies also have four subclasses. There is a correlation between murine and human IgG subtypes: Human lgGl<->Murine lgG2a; Human lgG2<->Murine lgG3; Human lgG3<->Murine lgG2b; Human lgG4<->Murine lgGl.(37) hlgGl/mlgG2a is against viral antigens; hlgG2/mlgG3 is against bacterial antigen, especially polysaccharides; hlgG3/mlgG2b is against intracellular bacteria; and hlgG4/mlgGl is related to parasite antigens.(17, 27, 76, 81)
Regulatory immune responses
Treg is the host immune inhibitory mechanism(35). It is driven by IL-2 and TGF beta. The main effector cells for Treg are TGFb producing CD4 T cell and IgA producing B cell. The key transcription factor for Treg pathway is STAT5, especially STAT5a. But, both STAT5a and STAT5b play non-redundant roles in Treg generation.(88) They may act sequentially with STAT5b activation first in THfh signaling. Combined STAT5b and STAT5a signaling induces the generation of Treg. The combination of Treg and the above four immunological pathways is important to shift adaptive immunity to tolerable immunity. During the initial infection, acute stage fierce cytokines can rapidly kill pathogens as well as infected cells or tissues. However, if the pathogen infects a lot of cells in a tissue such as liver, to kill the infected cells will total destroyed the organ.(86) Thus, regulatory T cells STAT5 signal combining TH1/TH2/TH22/THαß will make CD4 T cells with less fierce cytokines.(88) Then, TH1like/TH9/TH17/TH3 immunological pathways will be generated in more chronic stage. It is worth noting that there are two subtypes of IgA antibodies: IgA1 and lgA2. IgA1 is the dominant IgA antibody in serum, and lgA2 is the dominant IgA in mucosa. TGF beta can induce either IgA1 or lgA2 which seems to be dependent on lymphoid follicle location.(90) In GULTs or Peyer’s Patch, lgA2 is the dominant IgA antibody produced in Gl mucosa there. In lymph nodes of other body locations, IgA1 is the dominant IgA antibody produced there.(1) However, IgA1 is especially related to viral protein antigens and lgA2 is especially related to bacterial antigens such as LPS.(32) It is also worth noting that IL-13 is also a Treg related cytokine which is pro-fibrogenic and related to TGF beta signaling.(64, 83)
Tolerable immune responses
TH1-like cells (non-classic TH1) are initiated by TGF beta(STAT5 signaling) and IFNg(STAT4 signaling). TH1-like cells with Foxp3+ regulatory character are identified.(20, 62) There is a close relation to TH1 helper cells and TH1-like cells.(65, 69) TH1-Iike cells are the chronic host immunity of TH1 immune response. Thus, it could be related to chronic inflammation such as long-term tuberculosis infection. The effector cells of TH1-like immunity include suppressive macrophages (M2), suppressive CD8 T cells (EM3 CD27-CD28-), IgA1 producing B cells, and IFNg/TGFb producing CD4 T cells.(5, 28, 29, 70) TH1-like immunity induces type4 delayed-type hypersensitivity such as Crohn’s disease.(16)
TH9 cell is driven by IL-4 (STAT6 signaling) combining TGF beta(STAT5 signaling).(18, 25, 30) Thus, TH9 cell is closely related to TH2 immunological pathway. It is characterized by IL-9 secreting CD4 T cell. TH9 cells are found to be important in chronic allergic condition such as asthma. Thus, TH9 helper cell is the chronic T helper cells related to TH2 immunity. The effector cells of TH9 immunity include regulatory eosinophils(rEOS), basophils (for chronic allergy and secretary IgA mediated reaction), IL-9 producing CD4 T cells, and lgA2 producing B cells.(39) TH9 immunity induces type1 allergy including asthma.(6,39,42,53,63,68,77)
TH17 cell is driven by IL-6 / IL-1 combining TGF beta(14, 31). Thus, TH17 cell is closely related to TH22 immunological pathway. It is characterized by IL-17 secreting CD4T cell. TH17 cells are found to be important in chronic immune-complex mediated disease such as rheumatic arthritis. Then, TH17 helper cell is the chronic T helper cell related to TH22 immunity.(46) TGF beta with STAT5 can suppress the acute IL-22 producing cells and enhance the chronic IL-17 producing cells(48, 71). Because of the role of TGF beta in TH17 immunity, regulatory IL-17 producing cells are noted.(8, 85) The effector cells of TH17 immunity include regulatory neutrophils(N2), IL-17 producing CD4 T cells, and lgA2 producing B cells.(24, 32) TH17 immunity induces type3 immune-complex hypersensitivity including ulcerative colitis.(4, 54)
TH3 cells are driven by IL-10 and TGF beta.(11, 19) Thus, TH3 cells are closely related to THαβ immunological pathway. It also produces IL-10 as well as TGF beta. Thus, TH3 helper cell is important to chronic antibody dependent cellular cytotoxic hypersensitivity. TH3 cell is the chronic helper T cells corresponding to THαβ helper cell. The TH3 immune effector cells include IL-13 producing regulatory NK cells(CD56+CD16-NK2 cells), IL-10 and TGF beta secreting CD4T cells, suppressive CD8 T cells ( EM2 CD27+CD28-), and IgA1 producing B cells.(43, 67, 70, 80) IgA1 is produced in serum and is against viral protein antigens. TH3 immunity induces type2antibody dependent cytotoxic hypersensitivity including chronic stage of SLE.(10, 66)
Conclusions
This summary diagram: 4x2+2 immunological pathways are the whole pictures of host immunological pathways. There are four eradicable immune responses: TH1/TH2/TH22/THαß which are corresponding to four tolerable immune responses: TH1Like/TH9/TH17/TH3. It will match the four types of hypersensitivity. Then, we can clearly understand the detailed immune response against different pathogens as well as allergy/hypersensitivity.
Funding
There was no funding for the study of this review article.
Availability of data and materials
Not applicable
Author’s contribution
Wan-Chung Hu is completely responsible for the idea formation, literature research, and manuscript writing for this review study.
Ethics approval and consent to participants
Not applicable
Consent for publication
Not applicable
Competing interests
The author declares that he has no competing interests.
Author’s information
The author, Wan-Chung Hu, graduated as a MD from National Taiwan University. Then, he went to Department of International Health, Johns Hopkins University Bloomberg School of Public Health for study and got a vaccine science PhD. His PhD thesis is to study host immune reaction against malarial infection. He did postdoctorate study for cancer immunotherapy in Genomics Research Center, Academia Sinica, Taiwan. He finished PGY training in Mackay Memorial Hospital and Shin-Kong Memorial Hospital both in Taiwan. Then, he is currently in Department of Clinical Pathology, Far Eastern Memorial Hospital of Taiwan R.O.C. for resident training.
Acknowledgement
The author is very thankful for the instruction by Professors Alan Scott, Louis August Bourgeois, and Pien-Chien Huang in my PhD study in vaccine science track of Department of International Health of Johns Hopkins University Bloomberg School of Public Health. The author is also very grateful for the guidance of Professors Chi-Huey Wong and Alice, Lin-Tsing Yu in my postdoctorate research in Genomics Research Center of Academia Sinica, Taiwan. The author also thanks Drs. Fang-Yeh Chu, Chih-Chun Chang, and Ming-Chang Su’s help in the department of clinical pathology of Far Eastern Memorial Hospital. Thanks a lot for their very inspiring training.
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