Clinical Immunology Evelien Floor
HC8 Caput lectures
Tregs: past, present and future
The history of the elusive suppressor/regulatory T cells
In the 1970s the suppressor T cells were born. A molecule that was crucial for suppressor T cell
activation was identified: the I-J determinant. This molecule was expressed on T suppressor cells.
However, when MHC was identified I-J didn’t exist anymore. After that, T cells-involving suppressive
phenomena were attributed to T cells secreting immunosuppressive cytokines. In 1993 phenotypically
distinct subsets of CD4+ T cells were identified with a memory phenotype and suppressive effects.
Those cells were CD4+ and CD25+.
CD25 is the high affinity IL-2 receptor which is present on regulatory T cells. This IL-2 receptor is
constitutively active on Tregs. Later on, the transcription factor FOXP3 was identified. Mutations in
FOXP3 result in development of autoimmunity and allergy.
Therefore, it was named the master transcription factor
which programs the development and function of
CD4+CD25+ regulatory T cells.
There are two types of Tregs: thymus derived Tregs and
induced Tregs. Thymus derived Tregs are imprinted and
selected for a not too high and not too low avidity for self-
antigens. Tregs can also be induced by activation of FOXP3 in
the periphery. However, this has not been proven in humans
yet because after induction they lose the Treg epigenetics.
Mechanisms of suppression
A lot of cells can be suppressed by Tregs as they have a broad suppressive function. Every Treg works
different in different conditions:
1. Inhibitory cytokines
o IL-10, IL-35, TGF-b
2. Cytolysis
o Perforin, granzyme A and granzyme B
3. Metabolic disruption
o High-affinity CD25-dependent cytokine-deprivation-mediated apoptosis
o CD39- and/or CD73-generated, adenosine receptor 2A-mediated immunosuppression
o cAMP-mediated inhibition
4. Targeting dendritic cells
o LAG3-MHC-class-II-mediated suppression of DC maturation
o CTLA4-CD80/CD86-mediated induction of IDO (immunosuppressive molecule)
1
HC8 Caput lectures
Tregs: past, present and future
The history of the elusive suppressor/regulatory T cells
In the 1970s the suppressor T cells were born. A molecule that was crucial for suppressor T cell
activation was identified: the I-J determinant. This molecule was expressed on T suppressor cells.
However, when MHC was identified I-J didn’t exist anymore. After that, T cells-involving suppressive
phenomena were attributed to T cells secreting immunosuppressive cytokines. In 1993 phenotypically
distinct subsets of CD4+ T cells were identified with a memory phenotype and suppressive effects.
Those cells were CD4+ and CD25+.
CD25 is the high affinity IL-2 receptor which is present on regulatory T cells. This IL-2 receptor is
constitutively active on Tregs. Later on, the transcription factor FOXP3 was identified. Mutations in
FOXP3 result in development of autoimmunity and allergy.
Therefore, it was named the master transcription factor
which programs the development and function of
CD4+CD25+ regulatory T cells.
There are two types of Tregs: thymus derived Tregs and
induced Tregs. Thymus derived Tregs are imprinted and
selected for a not too high and not too low avidity for self-
antigens. Tregs can also be induced by activation of FOXP3 in
the periphery. However, this has not been proven in humans
yet because after induction they lose the Treg epigenetics.
Mechanisms of suppression
A lot of cells can be suppressed by Tregs as they have a broad suppressive function. Every Treg works
different in different conditions:
1. Inhibitory cytokines
o IL-10, IL-35, TGF-b
2. Cytolysis
o Perforin, granzyme A and granzyme B
3. Metabolic disruption
o High-affinity CD25-dependent cytokine-deprivation-mediated apoptosis
o CD39- and/or CD73-generated, adenosine receptor 2A-mediated immunosuppression
o cAMP-mediated inhibition
4. Targeting dendritic cells
o LAG3-MHC-class-II-mediated suppression of DC maturation
o CTLA4-CD80/CD86-mediated induction of IDO (immunosuppressive molecule)
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