Inducible Costimulator Protein (Icos) Controls T Helper Cell Subset Polarization after Virus and Parasite Infection

It has been shown that certain pathogens can trigger efficient T cell responses in the absence of CD28, a key costimulatory receptor expressed on resting T cells. Inducible costimulator protein (ICOS) is an inducible costimulator structurally and functionally related to CD28. Here, we show that in the absence of CD28 both T helper cell type 1 (Th1) and Th2 responses were impaired but not abrogated after infection with lymphocytic choriomeningitis virus (LCMV), vesicular stomatitis virus (VSV), and the nematode Nippostrongylus brasiliensis. Inhibition of ICOS in CD28-deficient mice further reduced Th1/Th2 polarization. Blocking of ICOS alone had a limited but significant capacity to downregulate Th subset development. In contrast, cytotoxic T lymphocyte (CTL) responses, which are regulated to a minor and major extent by CD28 after LCMV and VSV infection, respectively, remained unaffected by blocking ICOS. Together, our results demonstrate that ICOS regulates both CD28-dependent and CD28-independent CD4+ subset (Th1 and Th2) responses but not CTL responses in vivo.

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Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis

Nature ◽

10.1038/nature20810 ◽

2017 ◽

Vol 542 (7639) ◽

pp. 110-114 ◽

Cited By ~ 303

Author(s):

Deepak A. Rao ◽

Michael F. Gurish ◽

Jennifer L. Marshall ◽

Kamil Slowikowski ◽

Chamith Y. Fonseka ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

B Cells ◽

Cell Subset ◽

T Helper Cell ◽

Helper Cell ◽

T Helper ◽

Helper Cell Subset

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Functionally distinct T-helper cell phenotypes predict resistance to different types of parasites in a wild mammal

10.1101/2021.03.15.435455 ◽

2021 ◽

Author(s):

Yolanda Corripio-Miyar ◽

Adam Hayward ◽

Hannah Lemon ◽

Amy R Sweeny ◽

Xavier Bal ◽

...

Keyword(s):

Flow Cytometry ◽

Cytokine Production ◽

Ex Vivo ◽

T Helper ◽

Adaptive Immune ◽

Wide Range ◽

Th2 Responses ◽

Different Types ◽

Th1 And Th2 Responses ◽

Th1 And Th2

1. The adaptive immune system is critical to an effective, long-lasting ability to respond to infection in vertebrates and T-helper (Th) cells play a key role in orchestrating the adaptive immune response. Laboratory studies show that functionally distinct Th responses provide protection against different kinds of parasites (i.e., Th1 responses against microparasites and Th2 against macroparasites). 2. Natural populations must deal with challenges from a wide range of infectious agents and co-infection with different types of parasite is the norm, so different Th responses are likely to play an important and dynamic role in maintaining host health and fitness. However, the relationship between T helper immune phenotypes and infection with different types of parasites remains poorly understood in wild animals. 3. In this study, we characterised variation in functionally distinct Th responses (Th1, Th2, Th17 and regulatory responses) in a wild population of Soay sheep using flow cytometry to detect Th-subset specific transcription factors, and ex vivo lymphocyte stimulation to quantify release of Th-associated cytokines. We specifically tested the prediction that raised Th1 and Th2 responses should predict reduced apicomplexan (coccidian) and helminth (nematode) parasite burdens, respectively. 4. Cell counts of different Th subsets measured by flow cytometry did not vary with age or sex. However, all measures of Th-associated ex vivo cytokine production increased with age, and Th17- and regulatory Th-associated cytokine production increased more rapidly with age in males than females. 5. Independent of age and sex, Th2-associated immune measures negatively predicted gastro-intestinal strongyle nematode faecal egg count, while production of the Th1-associated cytokine IFN-γ negatively predicted coccidian faecal oocyst count. 6. Our results provide important support from outside the laboratory that Th1 and Th2 responses confer resistance to different kinds of parasites (micro- and macro-parasites, respectively). They also add to mounting evidence from wild populations that Th1/Th2 trade-offs often observed in controlled laboratory experiments may not readily translate to more complex natural systems. 7. Our study illustrates that harnessing more specific reagents and tools from laboratory immunology has the potential to illuminate our understanding of epidemiology and host-parasite co-evolution in the wild.

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CD4 T Helper Cell Subsets and Related Human Immunological Disorders

International Journal of Molecular Sciences ◽

10.3390/ijms21218011 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8011 ◽

Cited By ~ 1

Author(s):

Xiaoliang Zhu ◽

Jinfang Zhu

Keyword(s):

Transcription Factor ◽

Immune System ◽

Immune Responses ◽

Critical Role ◽

Cell Subset ◽

Lymphoid Cells ◽

T Helper Cell ◽

Helper Cell ◽

Th2 Cells ◽

T Helper

The immune system plays a critical role in protecting hosts from the invasion of organisms. CD4 T cells, as a key component of the immune system, are central in orchestrating adaptive immune responses. After decades of investigation, five major CD4 T helper cell (Th) subsets have been identified: Th1, Th2, Th17, Treg (T regulatory), and Tfh (follicular T helper) cells. Th1 cells, defined by the expression of lineage cytokine interferon (IFN)-γ and the master transcription factor T-bet, participate in type 1 immune responses to intracellular pathogens such as mycobacterial species and viruses; Th2 cells, defined by the expression of lineage cytokines interleukin (IL)-4/IL-5/IL-13 and the master transcription factor GAΤA3, participate in type 2 immune responses to larger extracellular pathogens such as helminths; Th17 cells, defined by the expression of lineage cytokines IL-17/IL-22 and the master transcription factor RORγt, participate in type 3 immune responses to extracellular pathogens including some bacteria and fungi; Tfh cells, by producing IL-21 and expressing Bcl6, help B cells produce corresponding antibodies; whereas Foxp3-expressing Treg cells, unlike Th1/Th2/Th17/Tfh exerting their effector functions, regulate immune responses to maintain immune cell homeostasis and prevent immunopathology. Interestingly, innate lymphoid cells (ILCs) have been found to mimic the functions of three major effector CD4 T helper subsets (Th1, Th2, and Th17) and thus can also be divided into three major subsets: ILC1s, ILC2s, and ILC3s. In this review, we will discuss the differentiation and functions of each CD4 T helper cell subset in the context of ILCs and human diseases associated with the dysregulation of these lymphocyte subsets particularly caused by monogenic mutations.

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Biologicals targeting T helper cell subset differentiating cytokines are effective in the treatment of murine anti-myeloperoxidase glomerulonephritis

Kidney International ◽

10.1016/j.kint.2019.05.012 ◽

2019 ◽

Vol 96 (5) ◽

pp. 1121-1133 ◽

Cited By ~ 5

Author(s):

Poh-Yi Gan ◽

Amy Chan ◽

Joshua D. Ooi ◽

Jonathan Dick ◽

Kei Nagai ◽

...

Keyword(s):

Cell Subset ◽

T Helper Cell ◽

Helper Cell ◽

T Helper ◽

Helper Cell Subset

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Lipopolysaccharide-enhanced, Toll-like Receptor 4–dependent T Helper Cell Type 2 Responses to Inhaled Antigen

Journal of Experimental Medicine ◽

10.1084/jem.20021340 ◽

2002 ◽

Vol 196 (12) ◽

pp. 1645-1651 ◽

Cited By ~ 827

Author(s):

Stephanie C. Eisenbarth ◽

Damani A. Piggott ◽

James W. Huleatt ◽

Irene Visintin ◽

Christina A. Herrick ◽

...

Keyword(s):

Allergic Sensitization ◽

T Helper Cell ◽

Helper Cell ◽

Asthma Prevalence ◽

Cell Type ◽

T Helper ◽

Th2 Responses ◽

Helper Cell Type ◽

Lps Signaling

Allergic asthma is an inflammatory lung disease initiated and directed by T helper cells type 2 (Th2). The mechanism involved in generation of Th2 responses to inert inhaled antigens, however, is unknown. Epidemiological evidence suggests that exposure to lipopolysaccharide (LPS) or other microbial products can influence the development and severity of asthma. However, the mechanism by which LPS influences asthma pathogenesis remains undefined. Although it is known that signaling through Toll-like receptors (TLR) is required for adaptive T helper cell type 1 (Th1) responses, it is unclear if TLRs are needed for Th2 priming. Here, we report that low level inhaled LPS signaling through TLR4 is necessary to induce Th2 responses to inhaled antigens in a mouse model of allergic sensitization. The mechanism by which LPS signaling results in Th2 sensitization involves the activation of antigen-containing dendritic cells. In contrast to low levels, inhalation of high levels of LPS with antigen results in Th1 responses. These studies suggest that the level of LPS exposure can determine the type of inflammatory response generated and provide a potential mechanistic explanation of epidemiological data on endotoxin exposure and asthma prevalence.

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Faculty Opinions recommendation of Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727254238.793534739 ◽

2017 ◽

Author(s):

Hiroshi Takayanagi

Keyword(s):

Rheumatoid Arthritis ◽

B Cells ◽

Cell Subset ◽

T Helper Cell ◽

Helper Cell ◽

T Helper ◽

Helper Cell Subset

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Faculty Opinions recommendation of Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727254238.793532375 ◽

2017 ◽

Author(s):

Graham Ogg

Keyword(s):

Rheumatoid Arthritis ◽

B Cells ◽

Cell Subset ◽

T Helper Cell ◽

Helper Cell ◽

T Helper ◽

Helper Cell Subset

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Unequal Death in T Helper Cell (Th)1 and Th2 Effectors: Th1, but not Th2, Effectors Undergo Rapid Fas/FasL-mediated Apoptosis

Journal of Experimental Medicine ◽

10.1084/jem.185.10.1837 ◽

1997 ◽

Vol 185 (10) ◽

pp. 1837-1849 ◽

Cited By ~ 327

Author(s):

Xiaohong Zhang ◽

Thomas Brunner ◽

Laura Carter ◽

Richard W. Dutton ◽

Paul Rogers ◽

...

Keyword(s):

Fas Ligand ◽

Differential Regulation ◽

T Helper Cell ◽

Helper Cell ◽

T Helper ◽

Activation Induced Cell Death ◽

Fas Signaling ◽

Lag Period ◽

Th 1 ◽

Th1 And Th2

T helper cell (Th) 1, but not Th2, effectors undergo rapid Fas/Fas ligand (FasL)-mediated, activation-induced cell death upon restimulation with antigen. Unequal apoptosis is also observed without restimulation, after a longer lag period. Both effectors undergo delayed apoptosis induced by a non–Fas-mediated pathway. When Th1 and Th2 effectors are co-cultured, Th2 effectors survive preferentially, suggesting the responsible factor(s) is intrinsic to each population. Both Th1 and Th2 effectors express Fas and FasL, but only Th2 effectors express high levels of FAP-1, a Fas-associated phosphatase that may act to inhibit Fas signaling. The rapid death of Th1 effectors leading to selective Th2 survival provides a novel mechanism for differential regulation of the two subsets.

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