Self MHC (Major Histocompatibility Complex) restriction

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Self MHC (Major Histocompatibility
Complex) restriction
 Self MHC (Major Histocompatibility Complex) restriction is a cornerstone of
the adaptive immune system, particularly in how T cells recognize antigens
and mount immune responses. Below is a more detailed explanation of the
concept:
 1. Background of MHC Molecules
 MHC Class I: These molecules are expressed on all nucleated cells and
present endogenous (intracellular) peptides, such as those derived from
viruses or cancerous cells, to CD8+ cytotoxic T cells.
 MHC Class II: These molecules are expressed mainly on professional
antigen-presenting cells (APCs) such as dendritic cells, macrophages, and
B cells. They present exogenous (extracellular) peptides to CD4+ helper T
cells, which play a key role in orchestrating the immune response.

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2. The Concept of Self MHC Restriction
 T Cell Receptors (TCRs): T cells have TCRs that recognize a complex made up of
a peptide antigen bound to an MHC molecule. However, the TCRs are restricted
to recognizing antigens only when they are presented by self MHC molecules.
This means that a T cell from one individual will not recognize the antigen-MHC
complex if the MHC molecules come from another individual.
 Zinkernagel and Doherty’s Experiments (1974): This principle was first
demonstrated by Rolf Zinkernagel and Peter Doherty. In their experiments with
mice infected by a virus, they showed that T cells could only kill virus-infected
cells if those cells expressed the same MHC molecules as the T cells' origin. This
established that T cells are "restricted" to responding to antigens only in the
context of their own MHC.
 Experiment Summary: They infected two genetically distinct strains of mice with the
same virus. When they took T cells from one strain and tried to make them kill virus-
infected cells from the other strain, the T cells did not recognize the infected cells. This
demonstrated that T cells recognize a combination of antigen and self MHC.

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3. Thymic Education and Selection
• Positive Selection: During their development in the thymus, immature T cells must be
able to recognize self MHC molecules. T cells that can bind weakly to self MHC
molecules receive survival signals and are allowed to mature. This is called positive
selection and ensures that the T cell repertoire can interact with the body’s own MHC
molecules to respond to infections.
• Negative Selection: T cells that bind too strongly to self MHC-peptide complexes are
eliminated through a process called negative selection, which prevents the
development of autoimmune diseases by removing overly self-reactive T cells.
4. T Cell Activation
T cells are activated when they encounter an antigen-presenting cell (APC) displaying a
peptide bound to a self MHC molecule.
CD8+ T Cells: Recognize antigen presented by MHC Class I and are responsible for
killing infected or cancerous cells.
CD4+ T Cells: Recognize antigen presented by MHC Class II and help activate other
immune cells such as B cells (for antibody production), macrophages, and other T
cells.
Two Signals for Activation:
Signal 1: The T cell receptor (TCR) binds to the peptide-MHC complex.
Signal 2: A co-stimulatory signal from the APC, such as B7 binding to CD28 on the T cell,
ensures full activation and prevents autoimmunity.

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5. Why Self MHC Restriction is Important
• Preventing Autoimmunity: This system helps prevent T cells from attacking the body’s
own tissues. By requiring antigen presentation on self MHC molecules, it ensures that T
cells can only be activated if the body itself signals the presence of an infection or
abnormality.
• Transplant Rejection: Self MHC restriction is a major reason why organ transplants from
genetically different individuals are rejected. The recipient's T cells do not recognize the
donor’s MHC molecules as "self," leading to an immune attack against the transplanted
organ.
• Vaccine Design: Understanding MHC restriction helps in designing vaccines that ensure
antigens are effectively presented to T cells, triggering a robust immune response.
6. TCR-MHC Interactions at a Molecular Level
The T cell receptor (TCR) recognizes both the peptide antigen and the MHC molecule
itself. The TCR binds to a specific portion of the MHC molecule called the α-helices, while
also contacting the peptide held in the groove of the MHC. This dual recognition of both
peptide and MHC is essential for the activation of the T cell.
There are certain "anchor residues" within the peptide that are specifically bound by the
MHC molecule, and variations in these residues can influence which peptides are
presented and, therefore, which T cells are activated.

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7. Evolutionary Perspective
The MHC system is highly polymorphic, meaning that there are many different forms (alleles) of
MHC genes in the human population. This diversity ensures that a wide variety of pathogens can
be recognized by different individuals. Each person’s unique combination of MHC alleles
influences which antigens their immune system can recognize and respond to.
8. Clinical and Therapeutic Implications
• Immunotherapy: In cancer immunotherapy, the concept of self MHC restriction is vital. For
example, in CAR T-cell therapy, engineered T cells must recognize cancer antigens in the
context of the patient’s own MHC.
• Autoimmune Diseases: Failures in the processes of positive and negative selection, or
abnormalities in MHC molecules, can lead to autoimmune diseases where the immune
system mistakenly targets self tissues.
• Understanding self MHC restriction is fundamental in immunology, as it plays a central role in
both immune defense mechanisms and the regulation of immune tolerance.

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 Alloreactivity of T cells refers to the phenomenon where T cells from one individual
(the recipient) recognize and respond to MHC molecules from another genetically
distinct individual (the donor) as foreign, leading to an immune response. This is a
critical concept in the context of organ transplantation, graft rejection, and graft-
versus-host disease (GVHD). Alloreactivity is considered an exception to the principle
of self MHC restriction, where T cells are normally supposed to recognize antigens
only when presented by self MHC molecules.
 Key Concepts of Alloreactivity:
 Allogeneic Recognition:
 T cells typically recognize foreign peptides presented by self MHC molecules. However, in
the case of alloreactivity, T cells recognize non-self MHC molecules (allogeneic MHC) from
another individual as foreign.
 The high degree of polymorphism in MHC genes between individuals is a primary reason for
alloreactivity. The structural differences between MHC molecules of two individuals can be
sufficient to stimulate a strong immune response even if no foreign peptides are involved.
 Frequency of Alloreactive T Cells:
 A large fraction (1-10%) of a person’s T cell population is capable of responding to
allogeneic MHC molecules. This high frequency is in contrast to the low percentage of T cells
that respond to conventional foreign antigens.
 The reason for this high frequency is thought to be the structural similarity between self MHC-
peptide complexes and allogeneic MHC molecules, leading to cross-reactivity.

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Mechanisms of Alloreactivity:
Direct Allorecognition: In this process, T cells from the recipient directly recognize
intact allogeneic MHC molecules (with or without bound peptides) on the
surface of donor cells. This is the primary mechanism involved in acute transplant
rejection.
Example: A recipient’s CD8+ T cells may directly recognize donor MHC Class I
molecules on transplanted tissue as foreign and initiate a cytotoxic response.
Indirect Allorecognition: In this mechanism, the recipient’s antigen-presenting
cells (APCs) process and present peptides derived from donor MHC molecules
(and possibly other donor proteins) on the recipient’s own MHC molecules. This is
a slower process and is typically involved in chronic rejection.
Example: Recipient’s APCs internalize donor cells, process them, and present
donor MHC-derived peptides on their own MHC Class II molecules to
activate CD4+ helper T cells.
Semi-Direct Allorecognition: This is a hybrid mechanism where recipient APCs
acquire donor MHC molecules via mechanisms like trogocytosis or exosome
uptake. These donor MHC molecules are then presented intact on recipient
APCs and can be recognized by the recipient’s T cells.

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Types of Alloreactivity Responses:
Acute Graft Rejection:
Acute rejection is mediated by direct allorecognition. It occurs when recipient T cells
recognize donor MHC molecules (Class I or Class II) as foreign and attack the graft.
The CD8+ T cells directly kill graft cells presenting allogeneic MHC Class I, while CD4+ T
cells help in recruiting other immune cells like macrophages and B cells,
exacerbating the immune response.
Cytokines released by activated T cells amplify the immune response, contributing to
tissue damage and graft rejection.
Chronic Graft Rejection:
Chronic rejection involves indirect allorecognition and occurs over a longer period
(months to years). The response is usually mediated by CD4+ T cells, which recognize
donor-derived peptides on self MHC Class II molecules.
Chronic rejection is associated with fibrosis, vascular occlusion, and gradual loss of
graft function due to ongoing inflammation and tissue remodeling.
Graft-Versus-Host Disease (GVHD):
In GVHD, donor T cells present in the transplanted tissue (typically in bone marrow or
hematopoietic stem cell transplants) recognize the recipient’s tissues as foreign and
mount an immune attack.
This is a common complication in allogeneic bone marrow transplants and can lead
to severe damage to the skin, liver, gut, and other tissues of the recipient.
Donor T cells react to host MHC molecules, leading to both acute and chronic GVHD.

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Molecular Basis of Alloreactivity:
Alloreactivity occurs because T cell receptors (TCRs) recognize allogeneic
MHC molecules as foreign. This happens through several mechanisms:
Molecular Mimicry:
Structural Similarity: Some allogeneic MHC molecules may structurally
resemble the self MHC-peptide complexes that a TCR is normally selected
for in the thymus. Even though the allogeneic MHC is different, the TCR
may cross-react and bind to it as if it were a self-MHC with a foreign
peptide.
Peptide-Independent Recognition:
In some cases, the TCR can recognize and bind to the MHC molecule
itself, irrespective of the peptide bound within the MHC. This is more
common in direct allorecognition.
Peptide-Dependent Recognition:
In other cases, the TCR may recognize a peptide presented by an
allogeneic MHC molecule, leading to activation. This mechanism is often
associated with indirect allorecognition, where recipient T cells recognize
donor MHC-derived peptides presented by self MHC molecules on
recipient APCs.

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Evolutionary Perspective:
MHC Polymorphism:
The extreme polymorphism of MHC genes in the human population is thought to have
evolved as a defense mechanism to ensure that different individuals can present and
respond to a wide array of pathogens.
However, this same polymorphism creates barriers to transplantation, as MHC
mismatch between individuals is the main cause of alloreactivity.
Selection Pressure:
Over time, populations have developed diverse MHC alleles that can better handle
pathogen challenges, but this diversity also increases the likelihood of T cell
alloreactivity in transplantation scenarios.
Clinical Implications of Alloreactivity:
Organ Transplantation:
The main reason for graft rejection is T cell alloreactivity. To minimize this risk, MHC
matching between donor and recipient is crucial. The more similar the MHC alleles, the
less likely it is that the recipient’s T cells will recognize the donor's MHC molecules as
foreign.
Immunosuppressive drugs are used to dampen the immune response and prevent
rejection by inhibiting T cell activation.

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Graft-Versus-Host Disease (GVHD):
In bone marrow or hematopoietic stem cell transplantation, alloreactive T
cells from the donor can cause GVHD. T cell depletion strategies or the use of
immunosuppressive agents are common treatments to minimize this risk.
Transplantation Tolerance:
Researchers are exploring strategies to induce transplant tolerance, where
the recipient’s immune system accepts the graft without continuous
immunosuppression. This may involve modifying T cell responses to reduce
alloreactivity or promoting regulatory T cells that suppress immune responses
to the graft.
Cancer Immunotherapy:
Alloreactivity can also be leveraged in cancer treatment. For example, graft-
versus-leukemia (GVL) effect in bone marrow transplants occurs when donor
T cells recognize and destroy residual leukemia cells in the recipient, utilizing
alloreactivity for therapeutic benefit.

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Summary:
Alloreactivity is an immune response where recipient T
cells recognize non-self (allogeneic) MHC molecules
from a donor as foreign, leading to graft rejection or
GVHD.
It involves both direct recognition of intact donor
MHC molecules and indirect recognition of donor-
derived peptides presented on recipient MHC
molecules.
Alloreactivity is a major barrier to successful organ
transplantation, and minimizing MHC mismatch and
using immunosuppressive therapies are strategies to
reduce rejection.
This phenomenon highlights the balance between the
immune system's need to recognize pathogens while
avoiding harmful responses to foreign but beneficial
tissues, like transplanted organs.

Self MHC (Major Histocompatibility Complex) restriction

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