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Since the DNA rearrangement takes place in a relatively random manner, the specificity of antigen is not limited to pathogenic agents. The reactivity of T and B cells can be targeted toward self-antigens and/or harmless environmental antigens/food/commensal bacterium. To avoid self-reactivity, the immune system has multiple mechanisms to achieve immunological tolerance against self- and non-self antigens (meaning no-reactivity against specific antigens). What will impaired regulation of the immune system result in?

Impaired regulation of the immune responses results in autoimmune- or autoinflammatory-disorders either in a tissue specific or systemic manner (examples in table). We will go over the mechanism that underlies the immune regulation.


For the following autoimmune diseases describe the specificity of the pathogenic T cells.

-Type I (insulin-dependent) diabetes mellitus
-Rheumatoid arthritis
-Multiple sclerosis
-Inflammatory bowel disease
-Peripheral neuritis
-Autoimmune myocarditis

Type I (insulin-dependent) diabetes mellitus- islet cell antigens

Rheumatoid arthritis- unknown antigen in joint synovium

Multiple sclerosis- myelin basic protein, proteolipid protein

Inflammatory bowel disease- unknown

Peripheral neuritis- P2 protein of peripheral nerve myelin

Autoimmune myocarditis- myocardial proteins


What is immunological tolerance? Give a few examples.

non-responsiveness to specific antigens

antigens from the self-tissues, non-self antigens: foods, commensal bacterium, pregnancy.

Tolerance against antigens we are exposed to commonly (food, commensal bacterium) is important to maintain homeostasis of the immune system and prevent autoimmune disorders such as IBD or hyper-immune disorders (allergy)


How does chronic infection or anti-tumor immunity relate to immunological tolerance?

The development of tolerance to pathogen antigens can be catastrophic for the host, not being able to mount effective responses.

Chronic infection often accompanied by immunological tolerance against the infectious agents, leading to recurring infections.

Anti-tumor immunity is often impaired by immunological tolerance provoked by the tumor environment.


Describe the role of T cells.
What are they essential for?
Which T cells are required for tolerance against self-antigens?

T cells are the key regulator (and effectors) of the adaptive
immune responses.

They are essential for induction of antibody production for many antigens (T-dependent antigens), cell mediated pro-inflammatory responses, graft rejection, and cytotoxic response against intracellular pathogens.

A subset of T cells (called regulatory T cells) are required for tolerance against self-antigens. (foxp3+)

Slide 8


What are the two mechanisms of immune tolerance?

Describe/define both.
(Regulatory T cells, Myeloid Derived Suppressor cells, Inappropriate stimulation...)

central and peripheral

Central tolerance: This is based on elimination of T cells that are reactive to antigens present in the thymus---self antigens.

Peripheral tolerance:
Regulatory T cells—professional T cells that are designed to impose suppression to other immune cells.

Myeloid Derived Suppressor cells (MDSCs): A group of myeloid cells become potent immunoregulatory cells when exposed to inflammatory cytokines (e.g.IFN-γ) and blocks T cell responses. Often tumor associated.

Clonal anergy: When T cells are stimulated in a manner that are not “complete, cells become non-responsive to further stimulation.


What is anergy?

When T cells are stimulated in a manner that are not “complete, cells become non-responsive to further stimulation.

A. Anergy refers to the state of T cells that are unresponsive to antigen stimulation.

B. When naive T cells are presented antigens in the absence of the crucial “second signal (stimulation from CD28), cells get partially activated and undergoes the process that is dominated by degradation of signaling molecules required for activation and becomes non-responsive to further stimulation.

C. Ligand (CD80, CD86) for CD28 is expressed by a limited group of antigen presenting cells. Therefore, when antigen is presented by other type of cells (e.g. tumor cells), cells become anergic in vivo.


Describe clonal selection of self-reactive cells.

Intrathymic clonal deletion during the maturation process of thymocytes eliminate cells that have high affinity to antigens present in the thymus.

Slide 11


Describe AIRE gene. What does it do?

AIRE is a transcription factor that is expressed mainly in the medulla of the thymus. AIRE induces expression of a wide range of genes expressed by other organs (e.g. endocrine gland). This leads to negative selection of thymocytes reactive to these self antigens.

AIRE gene enables thymic stromal cells to express non-thymic genes (e.g. pancreas specific genes) and present self antigens to developing thymocytes.


What will loss of function of AIRE gene lead to?

Loss of functions of AIRE gene leads to severe auto-recessive genetic autoimmune disorder:

Autoimmune polyendocrine syndrome (APS). Endocrine organs are destructed by antibodies and lymphocytes.

Failure of Central tolerance:
Loss of functions of AIRE gene leads to severe auto-recessive genetic autoimmune disorder: Autoimmune polyendocrine syndrome (APS). Endocrine organs are destructed by antibodies and lymphocytes.


What are Hassall's corpuscles?

Hassall's corpuscles—is now defined as the site for generation of regulatory T cells. Cells that have intermediate affinity to self-antigens and not eliminated by negative selection

mature into Foxp3+ Tregs.

A group of thymocytes that have reactivity against self-antigens are converted into nTregs. This takes place in the structure called Hassall’s corpuscles.

Hassall's corpuscles are groups of epithelial cells within the thymic medulla. Human Hassall's corpuscles express thymic stromal lymphopoietin (TSLP) and help differentiation of FOXP3+ regulatory T cells via activation of a subset of dendritic cells.


Describe the suppression by innate cells.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that are defined by their myeloid origin and ability to potently suppress T cell responses.

They were initially recognized as cells that infiltrate solid tumors and have potent immune-suppressive functions. They suppress in part by response to pre-existing inflammations and activated by cytokines such as IFN-γ. Then in turn produce immuno-inhibitory factors


Describe the following types of T cell mediated tolerance.

Dominant suppression
Cell intrinsic activation.

1. Dominant suppression: imposed by professional regulators

2. Cell intrinsic inactivation: change of the state of T cells (become unresponsive to antigen stimulation)

Slide 16


Describe nTregs.

What is their role?
Where are they generated?

What do they express? What do mature nTregs also express?

thymus derived Foxp3+ cells. Mainly against self-antigens.

Enforcement by nTregs:
“professional” T regulators, aka “nTregs”. These are cells generated in the thymus and impose suppression of other immune cells, mainly T cells.

Since they are generated in the thymus due to relative high affinity against antigens present in the thymus, their antigen diversity is limited mostly to “self-antigens”.

They express a transcription factor called Foxp3. Foxp3 is essential for generation and/or maintenance of Tregs survival and functions. Mature nTregs also express CD25, IL-2R alpha chain. IL-2 is an essential factor for the maintenance of nTregs.


Describe iTregs.

How can they be influenced?

Which cytokines play critical roles in this case?

Which cytokine is inhibitory for induction of iTregs?

What factors can induce iTregs?

1. These Tregs can be manipulated by the environment (food), commensal organisms, pathogens and tumors

2. Like many other immune reactions, the cytokine milieu drives the differentiation of a naive T cell in the presence of its antigen. In this case, the presence of dominance of TGF-beta and IL-2 plays critical roles.

Presence of inflammatory cytokines such as IL-6 is inhibitory for induction of iTregs. iTregs are induced by antigen presenting cells that are present in the mucosal environment such as intestine.

Vitamin A and/or D functions as a co-factor to induce iTregs.


Describe Tr1 cells.

These cells produce immunosuppressive cytokine IL-10. TGF-b and IL-27 induces development of these cells. They are not Foxp3+ and categorized as a different subset of T cells. High levels of IL-10 presence is also sufficient to generate these Tr1 cells.


Which Treg's can be manipulated by food, commensal organisms, pathogens, tumors?

Which are periperal derived Foxp3+?

Which are thymus derived Foxp3+?

Which express high levels of IL-10?

Which mainly function against self-antigens?

Which are Foxp3 negative?

can be manipulated= iTregs

peripheral derived Foxp3+ cells. Mainly against foreign antigens

Tr1: peripheral derived Foxp3- cells. Express high levels of IL-10, an immunoregulatory cytokine.

nTregs: thymus derived Foxp3+ cells. Mainly against self-antigens.

Foxp3 negative- Tr1 cells


What is IPEX?

What will patients with IPEX suffer from?

IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome is characterized by systemic autoimmunity, typically beginning in the first year of life.

IPEX is cased by loss or dysfunction of Foxp3. Without aggressive immunosuppression or bone marrow transplantation, the majority of patients die within the first one to two years of life from metabolic derangements or sepsis.

Patients with IPEX suffer from multiple tissue damages caused by self-reactive T cells. The cause of this disease is mutations in a gene called foxp3. Foxp3 was found being expressed by a small fraction of CD4 T cells and lack of this gene caused loss of this fraction of T cells, suggesting the significance of Foxp3+ T cells for immune regulation.


How do Tregs suppress immune responses?

What do Fox3+ Tregs use to enchance their functions? What does Tr1 use?

What is another effector molecule generated by Tregs to suppress other lymphocytes?

Direct cell-cell contact is essential for Tregs to suppress target cells. CTLA-4 plays a significant role in the suppression by Tregs.

Foxp3+ Tregs use soluble factors (TGF-beta, IL-10) to enhance their functions. Tr1 mainly uses IL-10.

Adenosine is another effector molecule generated by Tregs to suppress other lymphocytes.


Describe CTLA-4. What is it expressed by? For what? What does it do?

What will its production prevent?

A. CTLA-4 is expressed by T cells after activation and competes with CD28 for B7 binding and will ultimately win the contest because it has higher affinity for B7 than does CD28. CTLA4 also recruits signaling molecules that suppress TCR signaling and blocks antigen-activation.

B. In the natural sequence of antigen activation of T cells, there is progressive increasing production of CTLA-4 as a regulatory mechanism to prevent runaway T cell proliferation.

C. CTLA4 mediated suppression plays a critical role in immune homeostasis evidenced by lethal autoimmune disorders observed in CTLA4 gene knock out mice.


How is CTLA4 related to autoimmunity and cancer immunotherapy?

Describe immune checkpoint blockade.

Inhibition of co-stimulation significantly improves the frequency of graft versus host disease (GVH) after bone marrow transplantations. This can be done by using CTLA-4 in a “trans” manner to block T cell activation form the outside. This is accomplished by the use of the man-made biologic modifier CTLA4-Ig, which is now also tested in clinical trial to treat autoimmune disorders.

Another recent application is called “immune checkpoint blockade”. Many co-stimulatory molecules (e.g. CTLA4) work in an inhibitory manner to T cells. For cancer immunotherapy, blocking these inhibitory molecules provoked robust anti-cancer immune responses and is now being tried clinically in many types of cancer.


Which T cells express CD28? Which express CTLA4?

all T cells express CD28. Only activated T cells and Tregs express CTLA4.