Antibody responses to glycolipid‐borne carbohydrates require CD4
            +
            T cells but not CD1 or NKT cells

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.

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Helios Expressing Regulatory T Cells are Correlated with Decreased IL-2 Producing CD8 T Cells and Antibody Diversity in Mozambican Individuals Living Chronically HIV-1

10.21203/rs.3.rs-778117/v1 ◽

2021 ◽

Author(s):

Raquel Matavele Chissumba ◽

Cacildo Magul ◽

Rosa Macamo ◽

Vânia Monteiro ◽

Maria Enosse ◽

...

Keyword(s):

T Cells ◽

B Cell ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Cell Function ◽

Antibody Responses ◽

Virologic Suppression ◽

Antibody Diversity ◽

Immune Alterations ◽

Hiv 1

Abstract Background: Human immunodeficiency virus type 1 (HIV-1) causes impairment of T and B cell responses, which begins during the acute phase of infection and is not completely restored by antiretroviral treatment. Regulatory T cell (Tregs) can improve overall disease outcome by controlling chronic inflammation, but may also suppress beneficial HIV-1 specific immune responses. We analyzed immune alterations, including Tregs, and their clinical significance in Mozambican people living chronically with HIV-1 (PLWH-C). Results: In PLWH-C, the proportion of total Tregs was positively correlated with the proportion of IL-2+CD4 T cells (r=0.647; p=0.032) and IL-2+IFNg+CD8 T cells (r=0.551; p=0.014), while the Helios+Tregs correlated inversely with levels of IL-2+CD8 T cells (r= -0.541; p=0.017). Overall, PLWH-C, with (82%) or without virologic suppression (64%), were seronegative for at least HIV-1 p31, gp160 or p24, and the breadth of antibody responses was positively correlated with proportions of CD38+HLA-DR+CD8 T cells (r=0.620; p=0.012), viral load (r=0.452; p=0.040) and inversely CD4 T cells count (r=-0.481; p=0.027). Analysis of all individuals living HIV-1 showed that the breadth of HIV-1 antibody responses was inversely correlated with the proportion of Helios+Tregs (r=-0.45; p=0.02). Conclusion: Among Mozambican patients living with HIV-1, seronegativity to some HIV-1 proteins is common mostly in virologically suppressed individuals. Low diversity of HIV-specific antibodies is correlated to indicators of disease control during ART. Elevation in the proportion of Helios+Tregs is related to a reduction of CD8 T expressing intracellular IL-2 but may contribute to impairment of B cell function.

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The transforming growth factor beta signaling pathway is critical for the formation of CD4 T follicular helper cells and isotype-switched antibody responses in the lung mucosa

eLife ◽

10.7554/elife.04851 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 28

Author(s):

Heather D Marshall ◽

John P Ray ◽

Brian J Laidlaw ◽

Nianzhi Zhang ◽

Dipika Gawande ◽

...

Keyword(s):

T Cells ◽

Transforming Growth Factor Beta ◽

Cd4 T Cells ◽

Transforming Growth Factor ◽

Antibody Responses ◽

T Follicular Helper Cells ◽

High Affinity ◽

Tfh Cells ◽

Helper Cells ◽

Follicular Helper

T follicular helper cells (Tfh) are crucial for the initiation and maintenance of germinal center (GC) reactions and high affinity, isotype-switched antibody responses. In this study, we demonstrate that direct TGF-β signaling to CD4 T cells is important for the formation of influenza-specific Tfh cells, GC reactions, and development of isotype-switched, flu-specific antibody responses. Early during infection, TGF-β signaling suppressed the expression of the high affinity IL-2 receptor α chain (CD25) on virus-specific CD4 T cells, which tempered IL-2 signaling and STAT5 and mammalian target of rapamycin (mTOR) activation in Tfh precursor CD4 T cells. Inhibition of mTOR allowed for the differentiation of Tfh cells in the absence of TGF-βR signaling, suggesting that TGF-β insulates Tfh progenitor cells from IL-2-delivered mTOR signals, thereby promoting Tfh differentiation during acute viral infection. These findings identify a new pathway critical for the generation of Tfh cells and humoral responses during respiratory viral infections.

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Enhanced oxidative phosphorylation in NKT cells is essential for their survival and function

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1901376116 ◽

2019 ◽

Vol 116 (15) ◽

pp. 7439-7448 ◽

Cited By ~ 17

Author(s):

Ajay Kumar ◽

Kalyani Pyaram ◽

Emily L. Yarosz ◽

Hanna Hong ◽

Costas A. Lyssiotis ◽

...

Keyword(s):

T Cells ◽

Glucose Metabolism ◽

Cell Survival ◽

Glucose Uptake ◽

Cell Fate ◽

Cd4 T Cells ◽

Cell Function ◽

Nkt Cells ◽

Nkt Cell ◽

And Function

Cellular metabolism and signaling pathways are key regulators to determine conventional T cell fate and function, but little is understood about the role of cell metabolism for natural killer T (NKT) cell survival, proliferation, and function. We found that NKT cells operate distinct metabolic programming from CD4 T cells. NKT cells are less efficient in glucose uptake than CD4 T cells with or without activation. Gene-expression data revealed that, in NKT cells, glucose is preferentially metabolized by the pentose phosphate pathway and mitochondria, as opposed to being converted into lactate. In fact, glucose is essential for the effector functions of NKT cells and a high lactate environment is detrimental for NKT cell survival and proliferation. Increased glucose uptake and IFN-γ expression in NKT cells is inversely correlated with bacterial loads in response to bacterial infection, further supporting the significance of glucose metabolism for NKT cell function. We also found that promyelocytic leukemia zinc finger seemed to play a role in regulating NKT cells’ glucose metabolism. Overall, our study reveals that NKT cells use distinct arms of glucose metabolism for their survival and function.

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