Understanding the Basics of Memory T Cells

When a virus enters the body, it is picked up by certain cells of the immune system. They transport the virus to the lymph nodes where they present its fragments, known as antigens, to CD8+ T cells responsible control of viral infections. Each of these cells carries a unique T cell receptor (TCR) on the surface that can recognize certain antigens. However, only very few T cell receptors match a given viral the antigen.

To bring the infection under control and maximize the defenses against the virus, these few antigen-specific T cells start dividing rapidly and develop into effector T cells. These kill virus-infected host cells and then die off themselves once the infection is cleared. 

Some of these short-lived effector cells—according to the generally accepted theory—turn into memory T cells, which persist in the organism long term. In case the same pathogen enters the body again, memory T cells are already present and ready to fight the invader more swiftly and effectively than during the first encounter.  

Now a new research has found that memory T cells may have been formed earlier than previously thought.^[17]

"Understanding the basis of effective long-term immune memory may help scientists develop better vaccines, understand differences among diseases and diagnose the quality of an individual person's immune responses," says Marc Hellerstein, professor of nutritional science and toxicology.^[13]

 

Immune Memory

Immune memory (or immunological memory), from either primary infection or immunization, is the source of protective immunity from a subsequent infection.^[3-5] Thus, COVID-19 vaccine development is closely tied to the topic of immunological memory.^[6,7]

A thorough understanding of immune memory to SARS-CoV-2 requires evaluation of its various components, including:^[2]

• B cells (aka B lymphocytes)
• CD8+ T cells (aka killer T-cells or cytotoxic T cells)
• CD4+ T cells (i.e., T helper cells)

as these different cell types may have immune memory kinetics relatively independent of each other. In this article, we will discuss memory T cell in the context of SARS-CoV-2 infection.

Studies of acute and convalescent COVID-19 patients have observed that T cell responses are associated with lessened disease, suggesting that SARS-CoV-2-specific CD4+ T cell and CD8+ T cell responses may be important for control and resolution of primary SARS-CoV-2 infection.

Pre-Existing Immunity

SARS-CoV-2 is a novel human pathogen. SARS-CoV-2 is a member of the coronavirus family that includes human coronaviruses (HCoVs) HCoV-OC43, HCoV-HKU1, HCoV-229E, and HCoV-NL63—betacoronaviruses and alphacoronaviruses that cause common colds.^[18] 

SARS-CoV-2 is relatively distantly related to those four endemic HCoVs, with <10% aa identity in the Spike RBD. As a result, 

• Cross-reactive circulating anti-Spike cross-neutralizing antibodies 
• Are rare^[2-6]
• Cross-reactive Spike memory B cells 
• Are rare
• Cross-reactive T cell memory^[7-9]
• Is reported in ∼28%–50% of people
• In a new study,^[24] it concludes that prior measles-mumps-rubella (MMR) or tetanus-diphtheria-pertussis (Tdap) vaccination may elicit cross-reactive T cells that mitigate COVID-19.
• The majority of the SARS-CoV-2 cross-reactive T cells are CD4+ T cells^[9]
• These have been demonstrated to be memory T cells and many are memory T cells to common cold coronaviruses with conserved epitopes^[10]
• Cross-reactive CD8+ T cells are observed less frequently.  But may still be biologically relevant.^[11]

The relatively slow course of severe COVID-19 in humans (median 19 days post-symptom onset (PSO) for fatal cases^[13]) suggests that protective immunity against symptomatic or severe 2° COVID-19 may very well involve memory compartments such as circulating memory T cells and memory B cells (which can take several days to reactivate and generate recall T cell responses and/or anamnestic antibody responses).^[14-16]

T Cell Memory

In the study of Shane Crotty et al,^[12] they assessed immune memory of all three branches of adaptive immunity (CD4+ T cell, CD8+ T cell, and humoral immunity) in a cross-sectional study of 185 recovered COVID-19 cases, extending out to greater than six months post-infection. 

Here are the summary of their results on SARS-CoV-2-specific memory of:

• B cells
• Overall, based on the observations, development of B cell memory to SARS-CoV-2 appeared to be robust and likely long-lasting
• Read [21] for more details.
• CD8+ T cells 
• The memory CD8+ T cell half-lives (or t_1/2) observed herein were comparable to the 123d t_1/2 observed for memory CD8+ T cells within 1-2 years after yellow fever immunization.^[10]
• Overall, the decay of circulating SARS-CoV-2-specific CD8+ T cell is consistent with what has been reported for another acute virus.
• CD4+ T cells
• Circulating SARS-CoV-2 memory CD4+ T cell responses were quite robust
• 94% of subjects with detectable circulating SARS-CoV-2 memory CD4+ T cells at 1 month PSO
• 89% of subjects with detectable circulating SARS-CoV-2 memory CD4+ T cells at ≥ 6 months PSO
• In individuals who recovered from mild COVID-19, CD4+ T cells gained a typical memory phenotype with high levels of expression of IL-7Rα.^[23]

Their findings have implications for immunity against 2° COVID-19, and thus the potential future course of the pandemic.^[19,20]

Compared with their naïve precursors, memory T cells are more abundant, have a lower threshold for activation, and more rapidly reactivate effector functions following antigen encounter. They are also maintained in barrier tissues to rapidly respond to reinfection. Thus, a major goal of vaccines is the induction of strong and durable T and B cell memory.

 

References

1. Adaptive immunity to SARS-CoV-2 and COVID-19
2. Amanat et al., 2020 A serological assay to detect SARS-CoV-2 seroconversion in humans
3. Okba et al., 2020 Severe acute respiratory syndrome coronavirus 2− specific antibody responses in coronavirus disease patients
4. Suthar et al., 2020 Rapid generation of neutralizing antibody responses in COVID-19 patients
5. Tan et al., 2020b A SARS-CoV-2 surrogate virus neutralization test based on antibody-mediated blockage of ACE2–spike protein–protein interaction
6. Wec et al., 2020 Broad neutralization of SARS-related viruses by human monoclonal antibodies
7. Le Bert et al., 2020 SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls
8. Braun et al., 2020 SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19
9. Grifoni et al., 2020 Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals
10. Mateus et al., 2020 Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans
11. Schulien et al., 2020 Characterization of pre-existing and induced SARS-CoV-2-specific CD8+ T cells
12. Immunological memory to SARS-CoV-2 assessed for greater than six months after infection
13. F. Zhou, T. Yu, R. Du, G. Fan, Y. Liu, Z. Liu, J. Xiang, Y. Wang, B. Song, X. Gu, L. Guan, Y. Wei, H. Li, X. Wu, J. Xu, S. Tu, Y. Zhang, H. Chen, B. Cao, Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 395, 1054–1062 (2020).
14. N. Baumgarth, J. Nikolich-Žugich, F. E.-H. Lee, D. Bhattacharya, Antibody Responses to SARS-CoV-2: Let’s Stick to Known Knowns. J Immunol, ji2000839 (2020).
15. A. Sariol, S. Perlman, Lessons for COVID-19 immunity from other coronavirus infections. Immunity. 53, 248–263 (2020).
16. D. M. Altmann, R. J. Boyton, SARS-CoV-2 T cell immunity: Specificity, function, durability, and role in protection. Sci Immunol. 5, eabd6160 (2020).
17. How the immune system remembers viruses: Memory T cells are formed earlier than previously thought
18. Human Coronavirus: Host-Pathogen Interaction
19. S. M. Kissler, C. Tedijanto, E. Goldstein, Y. H. Grad, M. Lipsitch, Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period. Science. 368, 860–868 (2020).
20. C. M. Saad-Roy, C. E. Wagner, R. E. Baker, S. E. Morris, J. Farrar, A. L. Graham, S. A. Levin, M. J. Mina, C. J. E. Metcalf, B. T. Grenfell, Immune life history, vaccination, and the dynamics of SARS-CoV-2 over the next 5 years. Science, eabd7343 (2020).
21. Understanding the Basics of Memory B Cells—The Antibody Factory
22. Coronavirus Deranges the Immune System in Complex and Deadly Ways
23. Neidleman, J. et al. SARS-CoV-2-specific T cells exhibit unique features characterized by robust helper function, lack of terminal differentiation, and high proliferative potential.
24. Protective heterologous T cell immunity in COVID-19 induced by the trivalent MMR and Tdap vaccine antigens
25. Antigenic drift: Understanding COVID-19 (good)

How Does SARS-CoV-2 Evade Our Immune System

Any virus that can cause disease in humans must have at least one immune evasion mechanism—at least one immune evasion “trick.” Without the ability to evade the immune system, a virus is usually harmless. 

In the case of SARS-CoV-2, the virus is clearly unusually effective at evading the triggering of early innate immune responses, such as type 1 interferons (IFNs) (see below). It is plausible that much of the nature of COVID-19 as an illness is a consequence of this one big trick of SARS-CoV-2.

Transient lymphopenia is a common feature of many respiratory viral infections, such as with influenza A H3N2 virus, human rhinovirus or respiratory syncytial virus, but lymphopenia in these other infections typically occurs for only 2–4 days around symptom onset and rapidly recovers. By contrast, COVID-19-associated lymphopenia may be more severe or persistent than in these other infections and seems to be more selective for T cell lineages.^[20]

Thus, although the mechanisms of lymphopenia in COVID-19 remain incompletely understood, the reduction in the number of T cells, in particular, in the periphery is a prominent feature of many individuals with severe disease.

 

Innate vs Adaptive Immune System

The immune system is broadly divided into:

• Innate immune system
• This immune response can occur within a couple of hours of infection.
• The innate immune response serves multiple purposes: 
• To slow down the viral replication and spread
• Restriction of viral replication within infected cells
• Creation of an antiviral state in the local tissue environment, including recruitment of effector cells of the innate immune system
• Priming the adaptive immune response
• Adaptive immune system
• This immune response can occur within ∼6–10 days after priming (see below)

Although the adaptive and innate immune systems are linked in important and powerful ways, they each consist of different cell types with different jobs.

An Idealized Immune Responses after a Viral Infection

In an idealized example of a generic viral infection, the following sequence of events happens (Figure 1A):^[1]

1. Innate immune system rapidly recognizes the infection and triggers the “alarm bells” of type I IFN expression and related molecules
• Children displayed higher basal expression of relevant pattern recognition receptors such as MDA5 & RIG-I in upper airway epithelial cells, macrophages & dendritic cells, resulting in stronger innate antiviral responses^[21] 
2. The adaptive immune responses are triggered
• Adaptive immune responses are slow due to:
• The inherent time demands for extensive proliferation and differentiation of naive cells into effector cells. 
• Once sufficient populations of effector T cells (helper T cells and cytotoxic T cells) and effector B cells (antibody secreting cells) have proliferated and differentiated, they often work together to rapidly and specifically clear infected cells and circulating virions.

Figure 1.  An integrated working model of COVID-19 immunology and disease severity

Specifics of SARS-CoV-2 infection

In a SARS-CoV-2 infection, the virus is particularly effective at avoiding or delaying triggering intracellular innate immune responses associated with type I and type III IFNs in vitro^[3] and in humans.^[3-6]  Without those responses, the virus initially replicates unabated and, equally importantly, the adaptive immune responses are not primed until the innate immune alarms occur (Figure 1B). 

• In an average case of COVID-19, a simple temporal delay in innate immune responses is enough to result in 
• Asymptomatic infection 
• ∼40% of SARS-CoV-2 infections are asymptomatic^[7] 
• Clinically mild disease 
• “Mild” is a COVID-19 clinical definition meaning not requiring hospitalization (Figure 1B). 
• If the innate immune response delay is too long—because of particularly efficient evasion by the virus, defective innate immunity, or a combination of both—then it will 
  result in conditions that lead to severe enough lung disease for hospitalization (Figure 1C). 
• Ineffective IFN innate immunity has been strongly associated with failure to control a primary SARS-CoV-2 infection and a high risk of fatal COVID-19
• Which was accompanied by innate cell immunopathology and a plasma cytokine signature of elevated CXCL10, interleukin (IL)-6, and IL-8 in many studies
• Impaired and delayed type I and type III IFN responses are associated with risk of severe COVID-19 

If the adaptive immune response starts too late, fatal COVID-19 appears to be a situation where viral burden is high^[13]in the absence of a substantive adaptive immune response (Figure 1C). The presence of T cells and antibodies is associated with successful resolution of average cases of COVID-19.^[8]

• It is suggested that T cell responses may be important for control and resolution of a primary SARS-CoV-2 infection.^[9-12]
• Most acute viral infections in humans induce the activation and proliferation of both CD4+ T cells and CD8+ T cells, so SARS-CoV-2 infection may not be unique in this regard.
•  However, hyperactivation or hypoactivation of T cells, or skewing towards an ineffective differentiation state (for example, Th17 cells, exhausted T cells or terminally differentiated T cells), might not be optimal in some patients with COVID-19. 
• It is plausible that the innate immune system tries to fill the vacuum left by the absence of a T cell response, attempting to control the virus with an ever-expanding innate immune response. 
• That solution ends up untenable, as a massive innate response results in excessive lung immunopathology. 
• This conclusion is consistent with many studies finding innate cytokine/chemokine signatures of immunopathology, and particularly observation of elevated frequencies of neutrophils (the most common cell type of the innate immune system) in blood,^[14] and massive numbers of neutrophils in lungs, associated with severe, end-stage COVID-19 disease.^[9,12,15,16]

• Elderly individuals have a smaller naive T cell pool 
• Elderly are therefore more likely to struggle to make a T cell response quickly that can recognize this new virus, which also likely results in hampered neutralizing antibody responses, because neutralizing antibody responses are generally T cell-dependent.

In contrast, end-stage disease is not generally associated with preferentially elevated T cell abundance in lung tissue^[9,17,18], consistent with a working model that early adaptive immune responses are very beneficial, and late adaptive immune responses are simply too late (Figure 1C).

References

1. Adaptive immunity to SARS-CoV-2 and COVID-19
2. Weaver C., Murphy K. Janeway’s Immunobiology. W.W. Norton, 2016
3. Blanco-Melo D., Nilsson-Payant B.E., Liu W.-C., Uhl S., Hoagland D., Møller R., Jordan T.X., Oishi K., Panis M., Sachs D., et al.  Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19.  Cell. 2020; 181: 1036-1045.e9
4. Arunachalam P.S., Wimmers F., Mok C.K.P.,Perera R.A.P.M., Scott M., Hagan T., Sigal N., Feng Y., Bristow L. Tak-Yin Tsang O. et al. Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans.  Science. 2020; 369: 1210-1220.
5. Bastard P., et al. HGID LabNIAID-USUHS Immune Response to COVID GroupCOVID CliniciansCOVID-STORM CliniciansImagine COVID GroupFrench COVID Cohort Study GroupMilieu Intérieur ConsortiumCoV-Contact CohortAmsterdam UMC Covid-19 BiobankCOVID Human Genetic Effort Autoantibodies against type I IFNs in patients with life-threatening COVID-19.  Science. 2020; 370: eabd4585
6. Laing A.G., et al. A dynamic COVID-19 immune signature includes associations with poor prognosis.  Nat. Med. 2020; 26: 1623-1635
7. Prevalence of asymptomatic SARS-CoV-2 infection: a narrative review.  DP Oran, EJ Topol - Annals of internal medicine, 2020
8. Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals.  A Grifoni, D Weiskopf, SI Ramirez, J Mateus, JM Dan… - Cell, 2020
9. Liao, et al.  Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19
10. Rydyznski Moderbacher et al., 2020 Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity
11. Sekine et al., 2020 Viral presence and immunopathology in patients with lethal COVID-19: a prospective autopsy cohort study
12. Zhou et al., 2020b Acute SARS-CoV-2 infection impairs dendritic cell and T cell responses
13. Magleby et al., 2020 Impact of SARS-CoV-2 viral load on risk of intubation and mortality among hospitalized patients with coronavirus disease 2019
14. Kuri-Cervantes et al., 2020 Comprehensive mapping of immune perturbations associated with severe COVID-19
15. Radermecker et al., 2020 Neutrophil extracellular traps infiltrate the lung airway, interstitial, and vascular compartments in severe COVID-19
16. Schurink et al., 2020 Viral presence and immunopathology in patients with lethal COVID-19: a prospective autopsy cohort study
17. Oja et al., 2020 Divergent SARS‐CoV‐2‐specific T‐and B‐cell responses in severe but not mild COVID‐19 patients
18. Szabo et al., 2020 Analysis of respiratory and systemic immune responses in COVID-19 reveals mechanisms of disease pathogenesis
19. Coronavirus Deranges the Immune System in Complex and Deadly Ways
20. T cell responses in patients with COVID-19
21. Pre-activated antiviral innate immunity in the upper airways controls early SARS-CoV-2 infection in children

Cytokines, Inflammation and Pain

Cytokines are a broad and loose category of small proteins (~5–20 kDa) important in cell signaling. They are key players in the regulation of the immune response, particularly during infections, inflammatory joint, kidney, vessel and bowel diseases, or neurological and endocrinological autoimmune diseases. 

Cytokines include:

• Lymphokine
• Cytokines made by lymphocytes
• Monokine
• Cytokines made by monocytes and macrophages
• Chemokine
• Cytokines with chemotactic activities
• Interleukin (ILs)
• Cytokines made by one leukocyte and acting on other leukocytes
• Interferons (IFNs)
• Interferons are a group of signaling proteins made and released by host cells in response to the presence of several viruses.
• Tumour necrosis factors

but not hormones or growth factors. Unlike hormones, cytokines are not stored in glands as preformed molecules, but are rapidly synthesized and secreted by different cells mostly after stimulation.

Figure 1. Cytokines act in networks or cascades. They are a category of signaling molecules that mediate and regulate immunity, inflammation, hematopoiesis, and many other cellular processes.

Cytokine Network

Cytokines act in networks or cascades.  Several different cell types coordinate their efforts as part of the immune system. Each of these cell types has a distinct role in the immune system, and communicates with other immune cells using secreted cytokines.

A given cytokine may be produced by more than one type of cell.  They act through cell surface receptors.  

Cytokines are produced by a broad range of cells, but the predominant producers are helper T cells (Th) and macrophages, including immune cells like:

• Macrophages
• Macrophages are phagocytic cells that are produced during an injury or infection.
• Macrophages phagocytose foreign bodies and are antigen-presenting cells, using cytokines to stimulate specific antigen dependent responses by B and T cells and non-specific responses by other cell types.
• B Cells
• Unlike T cells that can produce a large amount of cytokines upon activation, B cells require specific differentiation and activation conditions to produce cytokines.
• However, there are a large number of cytokines that act on B cells that play significant roles in the development, survival, differentiation and proliferation of B cells.
• T Cells
• Killer T cells can use cytokines to recruit other types of cells when mounting an immune response.
• Helper T cells also use cytokine signaling to influence regulatory B cells directly, and other cell populations indirectly.
• Mast cell
• Endothelial cells
• Fibroblasts, and
• Various stromal cells

The proliferation and activation of eosinophils, neutrophils and basophils respond to cytokines as well (see Figure 1).

Summary of cytokines and their functions

• 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, which enhances inflammatory functions that support viral clearance
• Innate mediators of Th1-driven pathology are powerful across diseases.^[14]
• Scientists 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.
• Th2 cytokines 
• Cytokines produced by Th2 T-helper cells
• Include IL-4 , IL-5, IL-6, IL-10, and IL-13
• IL-4 is the defining cytokines for Th2 cells
• Th17 cytokines
• include IL-17, TGF-beta, IL-6
• IL-17 is the defining cytokines for Th17 cells
• Th17 cells play a role in host defense against extracellular pathogens, particularly at the mucosal and epithelial barriers, but aberrant activation has been linked to the pathogenesis of various autoimmune diseases.^[13]

Cytokine	Family	Main sources	Function
IL-1β	IL-1	Macrophages, monocytes	Pro-inflammation, proliferation, apoptosis, differentiation
IL-4	IL-4	Th-cells	Anti-inflammation, T-cell and B-cell proliferation, B-cell differentiation
IL-6	IL-6	Macrophages, T-cells, adipocyte	Pro-inflammation, differentiation, cytokine production
IL-8	CXC	Macrophages, epithelial cells, endothelial cells	Pro-inflammation, chemotaxis, angiogenesis
IL-10	IL-10	Monocytes, T-cells, B-cells	Anti-inflammation, inhibition of the pro-inflammatory cytokines
IL-11	IL-6	Fibroblasts, neurons, epithelial cells	Anti-inflammation, differentiation, induces acute phase protein
IL-12	IL-12	Dendritic cells, macrophages, neutrophils	Pro-inflammation, cell differentiation, activates NK cell
IL-13	IL-13/ IL-4	Th2, CD4 cells, natural killer T cell, mast cells, basophils, eosinophils, nuocytes	Anti-inflammation; Central regulator in IgE synthesis, goblet cell hyperplasia, mucus hypersecretion, airway hyperresponsiveness, fibrosis and chitinase up-regulation; Also, a mediator of allergic inflammation and different diseases including asthma.
TNF-α	TNF	Macrophages, NK cells, CD4+lymphocytes, adipocyte	Pro-inflammation, cytokine production, cell proliferation, apoptosis, anti-infection, play a damaging role in many inflammatory diseases
IFN-γ	INF	T-cells, NK cells, NKT cells	Pro-inflammation, innate, adaptive immunity anti-viral
GM-CSF	IL-4	T-cells, macrophages, fibroblasts	Pro-inflammation, macrophage activation, increase neutrophil and monocyte function
TGF-β	TGF	Macrophages, T cells	Anti-inflammation, inhibition of pro-inflammatory cytokine production

 

Inflammation and Pain

Inflammation is part of the body’s defense mechanism and plays a role in the healing process. 

The cardinal signs of inflammation include: pain, heat, redness, swelling, and loss of function. 

While the sensation is a very individualized experience, inflammation typically causes pain because the swelling and buildup of tissue starts pressing against nerve endings. This pressure sends pain signals to the brain, causing discomfort.

There is significant evidence showing that certain cytokines/chemokines are involved in not only the initiation but also the persistence of pathologic pain by directly activating nociceptive sensory neurons. Certain inflammatory cytokines are also involved in nerve-injury/inflammation-induced central sensitization, and are related to the development of contralateral hyperalgesia/allodynia.

Cytokines are important in health and disease, specifically in host immune responses to infection, inflammation, trauma, sepsis, cancer, and reproduction.  Their functions also include:

• Modulate the balance between humoral and cell-based immune responses
• Regulate the maturation, growth, and responsiveness of particular cell populations
• Enhance or inhibit the action of other cytokines in complex ways

Pro-Inflammatory vs Anti-Inflammatory

There are both pro-inflammatory cytokines and anti-inflammatory cytokines:

• Proinflammatory cytokines 
• Inflammatory cytokines play a role in initiating the inflammatory response and to regulate the host defense against pathogens mediating the innate immune response. 
• Some inflammatory cytokines have additional roles such as acting as growth factors.
• They are produced predominantly by activated macrophages and are involved in the up-regulation of inflammatory reactions. 
• There is abundant evidence that certain pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α are involved in the process of pathological pain.
• Anti-Inflammatory cytokines
• Major anti-inflammatory cytokines include IL-1 receptor antagonist, IL-4, IL-10, IL-11, and IL-13. 
• IL-10 is considered a prototypical anti-inflammatory cytokine, and is the most widely studied of the anti-inflammatory interleukins.
• Lower levels of IL-10 have been observed in individuals diagnosed with multiple sclerosis when compared to healthy individuals.^[4]
• Due to a decrease in IL-10 levels, TNFα levels are not regulated effectively as IL-10 regulates the TNF-α-converting enzyme.^[5]
• As a result, TNFα levels rise and result in inflammation.^[6]
• TNFα itself induces demyelination of the oliodendroglial via TNF receptor 1, while chronic inflammation has been linked to demyelination of neurons.

LIF, IFN-α, IL-6, and TGF-β are categorized as either anti-inflammatory or pro-inflammatory cytokines, under various circumstances.

References

1. Cytokines, Inflammation and Pain
2. B cells responses and cytokine production are regulated by their immune microenvironment
3. Expression and Function of Anti-Inflammatory Interleukins: The Other Side of the Vascular Response to Injury
4. Ozenci V, Kouwenhoven M, Huang YM, Xiao B, Kivisäkk P, Fredrikson S, Link H (May 1999). "Multiple sclerosis: levels of interleukin-10-secreting blood mononuclear cells are low in untreated patients but augmented during interferon-beta-1b treatment". Scandinavian Journal of Immunology. 49 (5): 554–61. 
5. Brennan FM, Green P, Amjadi P, Robertshaw HJ, Alvarez-Iglesias M, Takata M (April 2008). "Interleukin-10 regulates TNF-alpha-converting enzyme (TACE/ADAM-17) involving a TIMP-3 dependent and independent mechanism". European Journal of Immunology. 38 (4): 1106–17.
6. Nakahara J, Maeda M, Aiso S, Suzuki N (February 2012). "Current concepts in multiple sclerosis: autoimmunity versus oligodendrogliopathy". Clinical Reviews in Allergy & Immunology. 42 (1): 26–34. 
7. Change in the ratio of interleukin-6 to interleukin-10 predicts a poor outcome in patients with systemic inflammatory response syndrome
8. Essential involvement of interleukin-8 (IL-8) in acute inflammation
• IL-8 plays a causative role in acute inflammation by recruiting and activating neutrophils.
• Neutrophil infiltration into inflammatory sites is one of the hallmarks of acute inflammation. 
9. The role of interleukin-8 in inflammation and mechanisms of regulation
10. Coronavirus Deranges the Immune System in Complex and Deadly Ways
11. The role of IL-13 and its receptor in allergy and inflammatory responses
12. Annunziato F, Cosmi L, Liotta F, et al. Human Th1 dichotomy: origin, phenotype and biologic activities. Immunology 2014.
• IFN-γ is the most important cytokine, that is associated with the Th1 immune response.
13. Awasthi A, Kuchroo VK (2009) Th17 cells: From precursors to players in inflammation and infection. Int Immunol 21:489–498.
14. Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy