Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases

Heterotrimeric G proteins are key players in transmembrane signaling by coupling a huge variety of receptors to channel proteins, enzymes, and other effector molecules. Multiple subforms of G proteins together with receptors, effectors, and various regulatory proteins represent the components of a highly versatile signal transduction system. G protein-mediated signaling is employed by virtually all cells in the mammalian organism and is centrally involved in diverse physiological functions such as perception of sensory information, modulation of synaptic transmission, hormone release and actions, regulation of cell contraction and migration, or cell growth and differentiation. In this review, some of the functions of heterotrimeric G proteins in defined cells and tissues are described.

https://www.physiology.org/doi/pdf/10.1152/physrev.00003.2005

Mammalian G proteins and their cell type specific functions

Oral tolerance: immune mechanisms and treatment of autoimmune diseases

Lymphocytes in the human gastric mucosa during Helicobacter pylori have a T helper cell 1 phenotype

Upon microbial infection, specific Th1 or Th2 responses develop depending on the type of microbe. Here, we demonstrate that different microbial compounds polarize the maturation of human myeloid dendritic cells (DCs) into stably committed Th1 cell-promoting (DC1) or Th2 cell-promoting (DC2) effector DCs that polarize Th cells via different mechanisms. Protein extract derived from the helminth Schistosoma mansoni induced the development of DC2s that promote the development of Th2 cells via the enhanced expression of OX40 ligand. Likewise, toxin from the extracellular bacterium Vibrio cholerae induced development of DC2s as well, however, via an OX40 ligand-independent, still unknown mechanism. In contrast, toxin from the intracellular bacterium Bordetella pertussis induced the development of DC1s with enhanced IL-12 production, which promotes a Th1 cell development. Poly(I:C) (dsRNA, mimic for virus) induced the development of extremely potent Th1-inducing DC1, surprisingly, without an enhanced IL-12 production. The obtained DC1s and DC2s are genuine effector cells that stably express Th cell-polarizing factors and are unresponsive to further modulation. The data suggest that the molecular basis of Th1/Th2 polarization via DCs is unexpectedly diverse and is adapted to the nature of the microbial compounds.

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Microbial Compounds Selectively Induce Th1 Cell-Promoting or Th2 Cell-Promoting Dendritic Cells In Vitro with Diverse Th Cell-Polarizing Signals

Antigen-specific B cell responses to mucosally delivered proteins are dependent upon CD4-positive T helper (Th) cells, and the frequency of Th1 and Th2 cell responses after oral immunization may determine the level and isotype of mucosal antibody responses. We have used a protein-based vaccine, tetanus toxoid (TT), together with the mucosal adjuvant cholera toxin (CT), for oral immunization of mice to study the nature of antigen-specific Th cell subsets induced in Peyer's patches (PP) of the gastrointestinal (GI) tract and in the spleen (SP) during peak antibody responses. Mice orally immunized with TT and CT responded with antigen-specific secretory immunoglobulin A (S-IgA) antibodies in the GI tract, and with both IgG and IgA antibody responses in serum. PP and SP CD4+ T cells from mice orally immunized with TT plus CT were cultured with antigen-coated latex microspheres for induction of proliferative responses and for enumeration of cytokine producing CD4+ T cells. Interestingly, both PP and SP CD4+ T cell cultures showed increased numbers of IL-4- and IL-5 (Th2-type)-producing, spot-forming cells (SFCs) after 21 d of immunization, while essentially no interferon-gamma (IFN-gamma) or IL-2 (Th1-type) SFCs were noted. Cytokine-specific Northern blots and RT-PCR also revealed that significant IL-4 and IL-5 mRNA levels, but not IFN-gamma or IL-2 mRNA, were present in CD4+ T cells isolated from antigen-stimulated cultures. However, systemic immunization with TT and CT induced antigen-specific IgG and IgM but not IgA antibodies in serum. Further, both IL-2 and IFN-gamma-producing Th1-type cells as well as IL-4- and IL-5-secreting Th2-type cells were generated in SP. Our results show that oral immunization with TT and the mucosal adjuvant CT selectively induced antigen-specific Th2-type responses which may represent the major helper cell phenotype involved in mucosal IgA responses in the GI tract.

https://rupress.org/jem/article-pdf/178/4/1309/1104200/1309.pdf

Helper T cell subsets for immunoglobulin A responses: oral immunization with tetanus toxoid and cholera toxin as adjuvant selectively induces Th2 cells in mucosa associated tissues.

Abstract Objective: To evaluate immunological response to Covid-19 vaccines in immunocompromised haematology patients and compare with immunocompetent healthy controls Design: We compared total Anti SARS CoV 2 spike antibody and T cell response in 45 immunocompromised haematology patients with 30 healthy adults following 2 doses of Covid 19 vaccine for 3 to 5 months at 30 day intervals Setting: University Hospital, United Kingdom, Single Centre, March 2021 to December 2021 Main Outcome measures: Peak quantitative spike-specific antibody and cellular responses Results: We found 1. Non significant difference in T cell and total Anti SARS CoV 2 S antibody response between study and control group patients 2. Six (13%) study group participants did not have detectable Total Anti SARS Cov 2 S antibodies at any time point throughout the study monitoring period. 3. Three (7%) of the study group participants had no response, even after additional booster doses of Covid-19 vaccine. 4. All (100%) of the control group had detectable Anti SARS Cov 2 S antibodies after 2 doses of Covid 19 vaccine. 5. No participant died or was hospitalised due to severe Covid-19 infection during the study period. This included study group participants who had no antibody response at any time point. Conclusions: Though there was a non significant difference in T cell and total Anti SARS CoV 2 S antibody response between immunocompromised patients and healthy controls this did not result in any severe infection or Covid 19 related mortality in our study cohort. We did not identify any patient-specific factor (age, gender), specific haematological condition or treatment as determinant of response. Covid-19 vaccination was well tolerated without major side effects in both groups. What was already known about this topic: prior to starting this study there were no studies to confirm immunological response following Covid 19 vaccination in immunocompromised haematology patients. During the conduct of our study there have been publications from researchers confirming blunted serological response in 62-66% of immunocompromised haematology patients compared to 74 to 95% in healthy controls. What this study adds: Our study did not identify a significant difference in serological or T cell response between immunocompromised and healthy groups. Though 13% of immunocompromised patients had no response to Covid-19 vaccination none of them suffered from severe Covid-19 infection. We believe T cell response to Covid-19 vaccination has an important role in providing protective efficacy against Covid 19.

A single-centre, observational study to evaluate immune response to Covid-19 vaccines in immunocompromised patients with haematological disorders (COVAC-IC)

S Pillai

Papers

Helper T cell subsets for immunoglobulin A responses: oral immunization with tetanus toxoid and cholera toxin as adjuvant selectively induces Th2 cells in mucosa associated tissues.

A single-centre, observational study to evaluate immune response to Covid-19 vaccines in immunocompromised patients with haematological disorders (COVAC-IC)