T cells in Human Disease

Our immune system plays a crucial role in protecting our body against pathogens, but sometimes there is an exaggerated response. This exaggerated response is triggered by the interaction of the immune system with an antigen (allergen) and is referred to as hypersensitivity. Hypersensitivity is believed to be the cause of allergy and some auto-immune disease.

In this article, we will discuss mainly Type IV Hypersensitivity.

Classification	Immunoreactants	Clinical Presentation
Type I	Mast cell mediated, IgE dependent (anaphylactic, and IgE independent)	Anaphylaxis, urticaria, angioedema, sthma, and hay fever
Type IIa	Antibody-mediated cytotoxic reactions (IgG and IgM antibodies complement often involved)	Immune cytopenias
Type IIb	Antibody-mediated cell-stimulating reactions	Graves disease and chronic idiopathic urticaria
Type III	Immune complex–mediated reactions complement involved	Serum sickness and vasculitis
Type IVa	Th1 cell-mediated reactions macrophage activation	Type 1 diabetes and contact dermatitis (with IVc)
Type IVb	Th2 cell–mediated reactions eosinophilic inflammation	Persistent asthma and hay fever
Type IVc	Cytotoxic T cell-mediated	Stevens-Johnson syndrome and toxic epidermal keratinocytes (TEN)
	(perforin/granzyme B involved)
Type IVd	T-cell-mediated neutrophilic inflammation	Acute generalized exanthematous pustulosis (AGEP) and Behcet disease

Table 1.  Classification of hypersensitivity reactions (Source: [21])

Hypersensitivity 

Hypersensitivity reactions are classified into four types by Coombs and Gell. The first three types are considered immediate hypersensitivity reactions because they occur within 24 hours.^[23,24] The fourth type is considered a delayed hypersensitivity reaction because it usually occurs more than 12 hours after exposure to the allergen, with a maximal reaction time between 48 and 72 hours.^[22] The four types of hypersensitivity are (see Table 1):

• Type I: reaction mediated by IgE antibodies
• Found in the linings of the respiratory tract and digestive system, as well as in saliva (spit), tears, and breast milk
• Type II: cytotoxic reaction mediated by IgG or IgM antibodies
• IgG is the most common antibody. It's in blood and other body fluids, and protects against bacterial and viral infections. IgG can take time to form after an infection or immunization.
• IgM is found mainly in blood and lymph fluid, which is the first antibody the body makes when it fights a new infection.
• Type III: reaction mediated by immune complexes
• Type IV: delayed reaction mediated by cellular response (i.e., T-cell mediated)
• T cell hyperactivity and inflammation frequently associate with an excess of Th1 and Th17 cytokines
• They are also play a principal role in tumor immunity and transplant rejection

It's important to note that the numeral allocation of hypersensitivity "types" does not correlate (and is completely unrelated) to the "response" in the Th model (i.e., Th1, Th2).

Type IV Hypersensitivity

A Type IV hypersensitivity reaction is mediated by T cells that provoke an inflammatory reaction against exogenous or endogenous antigens. In certain situations, other cells, such as monocytes, eosinophils, and neutrophils, can be involved. 

After antigen exposure, an initial local immune and inflammatory response occurs that attracts leukocytes. The antigen engulfed by the macrophages and monocytes is presented to T cells, which then becomes sensitized and activated. These cells then release cytokines and chemokines, which can cause tissue damage and may result in illnesses. 

Figure 1.  The current model of the pathogenesis of SLE (Source: [32])

Cytokines

Cytokines are small soluble mediators released by many immune cell subsets and tissues. Cytokines have very important roles in modulating both the innate and adaptive immune responses. Both a defect and an excess of cytokine production, as well as abnormal responsiveness of immune cells to cytokines, can favor the development of immune-mediated disease, suggesting the constant requirement of a fine balance among cytokines to maintain immune homeostasis.

Considering that Lupus is a multi-systemic autoimmune disease in which many immune cell subsets play a significant role in the disease pathogenesis, it is expected that cytokines belonging to more than one Th type may contribute to immune dysregulation and subsequent autoimmune abnormalities. Indeed, in Lupus the contribution of cytokines from each group has been linked to the development and/or progression of the disease.

Lupus is a complex and variable autoimmune disease that affects predominantly women of childbearing age. Hallmarks of disease include autoreactive T and B cells, immune complex deposition in tissues, and systemic activation of type I IFN signaling and cytokines.^[32]

Figure 2. Mechanisms of differentiation and major biological activities of classic T helper type 1 (Th1) cells (Source: [14]).  Pattern recognition receptors (PRRs) present on myeloid dendritic cells (mDCs; or Conventional dendritic cell) recognize the pathogen and are induced to its processing and to their migration to the regional lymph node, where they present pathogen peptides associated with class II MHC to naive CD4+ T cells. 

CD4+ T Helper Cells

CD4+ T helper cells are crucial for the functioning of an intact immune system owing to the diverse roles they play in both immune surveillance and protection against foreign pathogens. 

Our immune systems are fine tuned in such a way that the antigen in question stimulates a particular cytokine environment, which in turn activates precise transcriptional networks that induce differentiation towards a specific T helper (Th) cell pathway.

Underlying this flexibility is the capacity of naïve CD4+ T cells to differentiate into different effector subsets that are equipped with specific functions to eradicate the immediate threat. 

 

Th1 in Human Disease

T helper type 1 (Th1) cells are generally associated with the eradication of intracellular pathogens. However, uncontrolled Th1 responses were implicated in autoimmunity (i.e., type 1 diabetes and multiple sclerosis) and COVID-19 patients with severe disease.

Despite the reduced levels of CD4+, COVID-19 patients with severe disease had higher levels of Th1 CD4+ cells than patients with moderate disease.^[4,11]

Notes on Th1 cells and their associated diseases:

• Th1 cell differentiation^[14]
• Influenced by environmental cytokines (i.e., IL-12) produced by cells of the innate immune system (see Figure 2)
• The interaction between co-stimulatory molecules (i.e., CD40 and CD154) can also contribute to Th1 cell differentiation
• IL-18 is a proinflammatory cytokine that facilitates type 1 responses
•  In collaboration with IL-12, IL-18 stimulates Th1-mediated immune responses
• In principle, IL-18 enhances the IL-12-driven Th1 immune responses, but it can also stimulate Th2 immune responses in the absence of IL-12.
• Th1 cytokines
• Cytokines produced by Th1 T-helper cells include: IL-2, IFN-γ, IL-12  & TNF-β
• IFN-γ is the defining cytokines for Th1 cells^[12]
• IFN-γ is the most important cytokine, that is associated with the Th1 immune response.
• IFN-γ is one of the most important endogenous mediators of immunity and inflammation that utilizes the Jak-STAT pathway to activate STAT1.
• IFN-γ can be utilized by the host to regulate the balance between clearance of invading pathogens and limiting collateral damage to the host.
• It can either augment or suppress autoimmunity and associated pathology in a context- and disease-specific manner.
• It plays an important role in limiting tissue damage associated with acute infections and with chronic inflammation in autoimmune diseases such as inflammatory arthritis and experimental allergic encephalomyelitis (EAE).
• Pathogenic role
• Innate mediators of Th1-driven pathology are powerful across diseases
• Oral GlcNAc treatment in vivo inhibited myelin-antigen induced secretion of Th1 (IFN-γ and TNF-α) and Th17 (IL-17 and IL-22) cytokines that promote disease.^[13,30]
• Neutrophils were found to help to drive liver damage^[10]
• It is found that liver-resident Kupffer cells induced neutrophil-mediated liver toxicity by producing IL-12 and responding to IFN-γ. Inhibition of the neutrophil response limited liver toxicity.

Figure 3.  Mechanisms of differentiation of classic T helper type 2 (Th2) cells (Source: [19]).

Th2 in Human Disease

Th2 cells were heavily involved in responses against extracellular pathogens and parasites. However, aberrant Th2 responses were associated with allergy and asthma development.

Notes on Th2 cells and their associated diseases:

• Th2 cell differentiation^[19]
• Naïve T cells can develop into different subsets when facing different cytokine milieus. 
• In Th2 cells, GATA3 remodels IL-4 locus into a more accessible condition. Dec2 caused IL-2Rα up-regulation and can cooperate with GATA3 to enhance Th2 differentiation (see Figure 3).
• GATA3 directly activates ECM1 expression, and ECM1 blocks STAT5 phosphorylation by interaction with IL-2Rβ, by which the negative signal of S1Pr1 re-expression is released, and mature Th2 cells can egress lymph node under the calling of high level of S1P.
• Th2 cytokines 
• Cytokines produced by Th2 cells include: IL-4 , IL-5, IL-6, IL-10, and IL-13
• IL-4 is the defining cytokines for Th2 cells
• Pathogenic role 
• A shifting from Th1 to Th2 phenotype may be associated with the progression of HIV infection to full blown AIDS.
• Overproduction of Th2 cytokines typically promotes B-cell hyperactivity and humoral responses
• Th2 cells coupled with IL-4 interact with B cells to begin production of a large amount of IgE
• Secreted IgE circulates in the blood and binds to an IgE-specific receptor (i.e., FcεRI) on the surface of mast cells and basophils, which are both involved in the acute inflammatory response. The IgE-coated cells, at this stage, are sensitized to the allergen.
• Type 1 hypersensitivity require a Th2 response during helper T cell development
• Preventive treatments, such as corticosteroids and montelukast, focus on suppressing mast cells or other allergic cells (i.e., eosinophils and basophils); T cells do not play a primary role during the actual inflammatory response. 

Figure 4.  Mechanisms of differentiation and major biological activities of T helper type 17 (Th17) cells (Source: [14]).  

Th17 in Human Disease

Th17 cells play a role in host defense against extracellular pathogens (including fungi), particularly at the mucosal and epithelial barriers.^[13,16]  This is a recently discovered T helper cell subset, characterized by its production of IL-17. IL-23 promotes the expansion of these cells and Th17 cells have been linked to several inflammatory conditions such as arthritis and IBD.

Notes on Th17 cells and their associated diseases:

• Th17 cell differentiation^[14]
• Pattern recognition receptor-expressing dendritic cells (DCs) may also present the pathogen peptides associated with MHC II in the regional lymph node or in the lymphoid mucosal tissue to a different subset of naive CD4+ Th cells which express CD161.
• Upregulation of serum IL-23 strengthens the case for Th17 activity
• The secretion of IL-23 from antigen-presenting cells such as dendritic cells, which have been activated by the uptake and processing of pathogens, in turn activates Th17 cells.
• Th17 cells, which respond to other cytokine stimulations such as IL-1β or IL-18 in concert with IL-23 to produce Th-17 associated cytokines.
• Th17 cytokines
• Th17 cells produce IL-17A, IL-17F, IL-22, TGF−β and IL-6
• IL-17 is the defining cytokines for Th17 cells
• Exhibit high plasticity 
• Because they rapidly shift into the Th1 phenotype in the inflammatory sites
• In these sites there is usually a dichotomous mixture of classic and non-classic (Th17-derived) Th1 cells
• Th17 cells' rarity in the inflammatory sites
• There are at least two different limiting mechanisms:^[14]
• The poor ability to produce IL-2 in response to TCR signaling
• The reduced capacity to enter into the cell cycle
• Pathogenic role
• Th17 cells were thought to be the pathogenic cells in almost all chronic inflammatory disorders, and the role of Th1 cells, which had been shown to be important in hundreds of previous studies, was underscored or even seen as protective against the Th17-mediated inflammation.^[15]
• The major emphasis on the pathophysiology of murine Th17 cells was placed on their determinant or even exclusive pathogenic role in models of autoimmunity.^[17]
• This concept was immediately extrapolated to human disorders, which are considered as equivalent to the aforementioned murine models, such as multiple sclerosis, rheumatoid arthritis and Crohn’s disease, but also to psoriasis and contact dermatitis. 

Treg in Human Disease

CD4+CD25+Foxp3+ regulatory T cells (i.e., Tregs) play central role in regulation of immune responses to self antigens, allergens, and commensal microbiota as well as immune responses to infectious agents and tumors.  

A number of mechanisms contribute to the capacity of the immune system to discriminate self from non-self, which include:^[25]

• The removal of immature self-reactive lymphocytes by negative selection in the thymus
• Treg plays major role in inducing and maintaining peripheral self-tolerance and thus preventing immune pathologies

Notes on Tregs and their associated diseases:

• Tregs cell differentiation
• Tregs produced by a normal thymus are termed ‘natural’. Treg formed by differentiation of naïve T cells outside the thymus, i.e. the periphery, or in cell culture are called ‘adaptive’.
• Tregs express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4 cells.
• Because effector T cells also express CD4 and CD25, Tregs are very difficult to effectively discern from effector CD4+, making them difficult to study. 
• Cytokine TGF−β is a critical differentiation factor for the generation of Tregs and is important in maintaining Treg homeostasis.^[26]
• Tregs cytokines
• IL-2 is a cytokine necessary for the development of Treg cells in the thymus
• IL-2 is important for T cells proliferation and survival, but in the case of its deficiency, IL-15 may be replaced. However, Treg cells development is dependent on IL-2.
• Protective role
• Tregs can be targeted to control physiological and pathological immune responses, for example, by depleting them to enhance tumor immunity or by expanding them to treat immunological diseases. 
• Tregs inhibit autoimmunity and protect against tissue injury
• Tregs suppress activation, proliferation and cytokine production of CD4+ T cells and CD8+ T cells, and are thought to suppress B cells and dendritic cells.
• T cells without a specialized regulatory capacity may also compete for resources such as growth factors and MHC class II stimulation and thus have a regulatory role via this general mechanism of competition.
• Tregs have the ability to adsorb IL-2 from the microenvironments, thus being able to induce apoptosis of other T cells which need IL-2 as main growth factor.^[27]

Figure 5.  Differentiation of Tfh and Tph cells in humans (Source: [33])

Tfh in Human Disease

T follicular helper cells (Tfh) are a specialized subset of CD4+ T cells that were first identified in the human tonsil. They play a critical role in protective immunity helping B cells produce antibody against foreign pathogens.

Tfh cells specifically support B­ cell differentiation by producing IL­21 and receptor engagement in the germinal center. Expansion of the Tfh cell subset has been described in several mouse models of lupus and increased levels of Tfh cells correlate with increased disease activity and severity in patients with SLE.

Notes on Tfh and their associated diseases:

• Tfh cell differentiation
• Peripheral helper T (Tph) cells vs T follicular helper (Tfh) cells
• While Tfh cells are found primarily in the secondary lymphoid organs, a small proportion circulate in the blood and are Tph.
• Due to the location of Tfh cells in secondary lymphoid organs, the study of these cells in humans has been difficult
• The differentiation mechanism is partly shared between Tph and Tfh cells in humans, and both Tfh and Tph cells can be found within the same tissues, including cancer tissues. However, Tph cells display features distinct from those of Tfh cells, such as the expression of chemokine receptors associated with Tph cell localization within inflamed tissues and a low Bcl-6/Blimp1 ratio.^[33] 
• Unlike that of Tfh cells, current evidence shows that the target of Tph cells is limited to memory B cells. 
• Smad2 and Smad3 activation by TGF−β and Activin A is vital for the differentiation of naïve CD4+ T cells into Tfh and Tph cells (see Figure 5). 
• Tfh cytokines
• Tfh cells produce high amounts of the cytokine IL-21 in the B cell follicles. 
• These molecules are not only determinative of the commitment of Tfh cells but are also pivotal for the migration and full functionality of these cells in follicles.
• Protective role
• Tfh cells prime B cells to initiate extrafollicular and germinal center antibody responses and are crucial for affinity maturation and maintenance of humoral memory. 
• In addition to the roles that Tfh cells have in antimicrobial defense, in cancer, and as HIV reservoirs, regulation of these cells is critical to prevent autoimmunity. 
• Pathogenic role
• Tfh function has been shown to be dysregulated in a number of diseases of excessive or insufficient antibody production. 
• Circulating Tfh numbers have been shown to increase in number in the blood of patients with autoimmune diseases, including lupus and rheumatoid arthritis. 
• Patients with common variable immunodeficiency caused by ICOS deficiency have been shown to have severely reduced circulating Tfh and major defects in antibody generation. 
• Defects in Tfh help to B cells has been observed in HIV infected patients and contributes to the inability of patients to produce effective HIV specific antibodies.

Given the contribution of Tfh to a number of human diseases, better understanding of these cells could one day be therapeutically beneficial. Furthermore, the production of long lasting specific antibodies forms the basics of successful vaccination, therefore a great deal of research is being carried out to better understand Tfh to improve vaccine design.

References

1. T follicular helper cells (British Society for Immunology)
2. Regulatory T Cells (British Society for Immunology)
3. Th1 and Th2 Lymphocytes in Autoimmune Disease
4. COVID-19 poses a riddle for the immune system
5. Zhang, X. et al. Nature 583, 437–440 (2020)
6. Lymphopenia in severe coronavirus disease-2019 (COVID-19): systematic review and meta-analysis
7. Antibodies against human endogenous retrovirus K102 envelope activate neutrophils in systemic lupus erythematosus
8. Expanding Role of T Cells in Human Autoimmune Diseases of the Central Nervous System (good)
9. Th17 cytokines in mucosal immunity and inflammation
10. Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy
11. Immune Responses Dictate COVID-19 outcome
12. Cross-regulation of Signaling and Immune Responses by IFN-γ and STAT1
13. N-Acetylglucosamine Inhibits T-helper 1 (Th1)/T-helper 17 (Th17) Cell Responses and Treats Experimental Autoimmune Encephalomyelitis
14. Human T helper type 1 dichotomy: origin, phenotype and biological activities
15. Tato CM, Laurence A, O’Shea JJ. Helper T cell differentiation enters a new era: le roi est mort; vive le roi ! J Exp Med. 2006;203:809–12.
16. Ouyang W, Kolls JK, Zheng Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity. 2008;28:454–67.
17. Gutcher I, Becher B. APC-derived cytokines and T cell polarization in autoimmune inflammation. J Clin Invest. 2007;117:1119–27.
18. Clerici M. Shearer GM: a TH1 to TH2 switch is a critical step in the etiology of HIV infection. Immunol Today. 1993;14:412–7.
19. Current understanding of Th2 cell differentiation and function (pdf)
20. Type IV Hypersensitivity Reaction
21. The Gell-Coombs Classification of Hypersensitivity Reactions
22. Pichler WJ. Delayed drug hypersensitivity reactions. Ann Intern Med. 2003 Oct 21;139(8):683-93. 
23. Justiz Vaillant AA, Vashisht R, Zito PM. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Dec 30, 2020. Immediate Hypersensitivity Reactions. 
24. Usman N, Annamaraju P. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Dec 14, 2020. Type III Hypersensitivity Reaction. 
25. Regulatory T cells in human disease and their potential for therapeutic manipulation
26. Chen W (August 2011). "Tregs in immunotherapy: opportunities and challenges". Immunotherapy. 3 (8): 911–4.
27. Pandiyan, Pushpa; Zheng, Lixin; Ishihara, Satoru; Reed, Jennifer; Lenardo, Michael J (4 November 2007). "CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation–mediated apoptosis of effector CD4+ T cells". Nature Immunology. 8(12): 1353–1362.
28. Defects in Regulatory T Cells Due to CD28 Deficiency Induce a Qualitative Change of Allogeneic Immune Response in Chronic Graft-versus-Host Disease
29. Regulatory T Cells and Foxp3
30. Association of a Marker of N-Acetylglucosamine With Progressive Multiple Sclerosis and Neurodegeneration
31. Human T follicular helper (Tfh) cells and disease
32. New insights into the immunopathogenesis of systemic lupus erythematosus
33. Shared and distinct roles of T peripheral helper and T follicular helper cells in human diseases
34. Regulatory T Cells and Human Disease
35. Designing spatial and temporal control of vaccine responses (good)