Hdm Tbl 8 - Cell-Mediated Immunity

Front 1

Difference between Mature and Naive T-Cell

Back 1

Mature T-Cells have just finished maturing in Thymus.

They are now NAIVE: Have TCRs specific to antigens, but NO EFFECTOR FUNCTION.

Front 2

How does a Naive T-Cell gain Effector Function?

Back 2

Naive T-Cells (circulating in the blood/lymph) enter a secondary immune organ (lymph node) to encounter an antigen, ACTIVATE, and proliferate.

Front 3

CCL18/19

Back 3

Secreted by APCs, produce a gradient to pull Naive T-Cells into secondary immune organs (Lymph Nodes).

Front 4

3 Major Steps of T-Cell Activation

Back 4

1. Pathogen (processed by Dendritic Cell) binds to DC PAMP Receptor.

2. Dendritic Cell then traffics into LYMPH NODE, following CCL21 Gradient.

3. In Lymph Node, DC secretes CCL18 and CCL19, triggering chemotaxis of Naive T-Cells.

4. Naive T-Cells enter Lymph Node, test their TCRs on presented antigen:MHC complex.

Front 5

Adhesins

Back 5

Slow naive T-Cell down after they approach the lymph node so that they enter and test their TCRs against the APCs antigen:MHC complex.

Front 6

What 3 things are required for Naive T-Cell activation?

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TCR, Co-Receptor, and Co-Stimulatory Receptor Activity

Front 7

What are the T-Cell Co-receptors?

Back 7

CD4+ for Helper T

CD8+ for Cytotoxic T

Front 8

CD28 Purpose. Relate to B7.

Back 8

Co-Stimulatory Receptor for T-Cells.

When a DC presents an antigen:MHC complex on its surface, CD28 on the Naive T-Cell binds to B7 on the Dendritic Cell as a scaffold.

CD28 Co-Stimulation induces survival of the Naive T-Cell with a TCR specific to the antigen.

Front 9

Anergy: Definition and what triggers it.

Back 9

Anergy is a state of unresponsiveness in T-Cells. They are inactivated when they attempt to respond to an antigen:MHC complex on a Dendritic Cell WITHOUT CD28 CO-STIMULATION.

Therefore, the non-specific T will not proliferate.

Front 10

Purpose of IL-2

Back 10

This Cytokine signals proliferation, differentiation, and effector function of T-Cells that have simultaneously bound TCR, Co-Receptor, and CD28 Co-Stimulatory Receptor.

Front 11

CD25: Purpose, what triggers it to express? Relate to Levels of Affinity.

Back 11

CD25 is the IL-2 Receptor.

Activated T-Cells signal transcription factor Nf-kB to produce IL-2 receptors.

CD25 has high-affinity and low-affinity forms. High-affinity is expressed in Activated T's, low-affinity is expressed in Naive T's so they remain hyporesponsive until exposure to a specific antigen:MHC complex.

Front 12

mAb Daclizumab and Basizlixbmab

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Monoclonal Antibody medications, target CD25 to block T-Cell Proliferation/Differentiation.

Front 13

What do Naive T-Cells undergo once activated?

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Differentiation into either Memory or Effector T-Cells.

Front 14

CD45: Purpose

Back 14

Different types of CD45 are clinical markers for levels of Naive, Effector, and Memory T-Cells.

Front 15

Memory T-Cells: Types

Back 15

Naive T-Cells activate, differentiate into either memory or effector T-Cells.

Memory T-Cells form either Effector Memory or Central Memory T-Cell Populations.

Front 16

Relate T-Cells and the Hayflick Limit

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Memory T-Cells senesnce with age due to telomere shortening. This is called the Hayflick Limit, and it impairs immunity after age 55.

Front 17

Effector Memory T-Cells

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Effector Memory T-Cells migrate to other tissues and lymph nodes to re-encounter their specific antigen and quickly differentiate to secrete inflammatory cytokines.

Promotes CELL-MEDIATED IMMUNITY by quickly differentiating into further T-Cells following antigen exposure.

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Central Memory T-Cells

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REMAIN IN SECONDARY IMMUNE ORGANS (LYMPH NODES).

Actin in HUMORAL IMMUNITY by activating B-Cells in resposne to their specific antigen exposure.

Front 19

CCR7 and CCR5

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CCR7 triggers chemotaxis of T-Cells to Lymph Nodes.

CCR5 triggers chemotaxis of T-Cells to Tissues.

Front 20

Which chemotaxis agent do Effector Memory T-Cells use?

Back 20

Use CCR7 to go to lymph nodes and CCR5 to go to tissues, searching for their specific antigen.

Front 21

What chemotaxis agents do Central Memory T-Cells use?

Back 21

Central Memory T-Cells upregulate humoral immunity by activating B-Cells to make antibodies in response to their specific antigen exposure.

They REMAIN IN LYMPH NODES, only use CCR7.

Front 22

Effector T-Cells: Origins and 3 Populations

Back 22

Naive T-Cells, upon binding to an antigen their TCR is specific to, differentiate further into either Memory or Effector T-Cells.

Effector T-Cells include Helper T, Cytotoxic T, and Regulatory T-Cell populations.

Front 23

Helper Effector T-Cells: Role and Co-Factor

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Helper T-Cells are CD4+, act as Gate Keepers in immune response.

Activate B-Cells, NK Cells, Neutrophils, Macrophages/DCs in response to antigen binding.

Contributes to both humoral and cell-mediated immunities.

Front 24

Th1 Cell Origin and Purpose. Relate to IL12, IFN-Gamma, Tbet.

Back 24

Naive T-Cells are triggered to differentiate into Th1 Helper CD4 T-Cells via IL12 secretion from Dendritic Cells, and IFN-Gamma from NK Cells. NK Cells drive transcription factor T-Bet expression.

Th1 Cells secrete IFN-Gamma and TNF-Alpha.

Critical role in clearance of Intracellular Pathogens and Cancer Cells.

Front 25

What does uncontrolled Th1 Polarization entail?

Back 25

Chronic inflammation, autoimmunity.

Front 26

What cell secretes IFN-Gamma? What functions does it have?

Back 26

Th1 CD4 Helper T-Cells secrete IFN-Gamma.

IFN-Gamma promotes B-Cell antibody secretion (IgG1, IgG3 to trigger complement and opsonization).

IFN-Gamma promotes protective Granuloma Formation in mycobacteria infected M1 Macrophages.

IFN-Gamma inhibits Th2 Responses.

Front 27

IL-12 Purpose and Origin

Back 27

Secreted from Dendritic Cells upon antigen phagocytization, triggers Naive T-Cells to differentiate into Th1 Cells.

Front 28

Th2 Cells: Purpose and Origin

Back 28

Role in allergy and parasite elimination.

Secretes Cytokines to promote Eosinophil, Basophil, Mast Cell, Goblet Cell responses.

Converts M1 -> M2 Macrophages (promotes healing).

Promotes B-Cell Antibody Secretion (IgE and IgG4).

Suppresses Th1 responses.

Front 29

Type 1 Hypersensitivity and Uncontrolled Th2 Polarization

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Allergic inflammation, promoted by Th2 CD4 Helper T-Cells.

Uncontrolled Th2 differentiation leads to ATOPY -> tendency to develop allergic disorders.

Front 30

IL-4 and IL-13 Purpose and Transcriptional Role

Back 30

Main Cytokines related to Th2 CD4 Helper T-Cells.

IL-4 (SECRETED BY NK T CELLS) triggers differentiation of Naive T-Cell into Th2 by driving GATA-3 transcription factor expression.

Drives all Th2 Cell Actions, except Eosinophil Action and Th1 Suppression.

Front 31

IL-5 Purpose

Back 31

Cytokine of Th2 Cells. Works with IL-4 to suppress Th1 response and granulocytes (IL-5 specifically triggers Eosinophils upregulation to attack Helminths/Parasites).

Front 32

Dupilumab

Back 32

mAb drug, targets IL-4/IL-13 to downregulate allergic reactions via Th2 Cells.

Front 33

IL-5 and IL-23 Purpose. Relate to RORyT.

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IL-5 and IL-23 secreted by Dendritic Cells drive Naive T-Cells to differentiate into Th17 CD4 Helper T-Cells.

They trigger expression of RORyT transcription factor to cause this transformation.

Front 34

Th17 CD4 Helper T-Cells: Role

Back 34

Critical role in elimination of Extracellular Bacteria and Fungi, BUT NOT PARASITES, mostly at epithelial barriers (skin/lungs/GI).

Front 35

IL-17 and IL-22 Purposes

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Both are the cytokines which cause Th17 CD4 Helper T-Cells to defend against extracellular bacteria and fungi at epithelial barriers.

IL-17 -> Activate Neutrophils directly, and aids in Neutrophil Recruitment.

IL-23 -> Activates Epithelial Cells to release AMPs, promotes epithelial tissue repair/healing/cell division.

Front 36

What does uncontrolled Th17 Proliferation cause?

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Autoimmunity, autoinflammatory disease involving skin barrier or mucosal tracts (Autoinflammatory Bowel Disease, Psoriasis).

Front 37

Secukinumab and Risankizumab

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Th17 mAb treatment drugs.

Secukinumab: anti-IL17

Risankizumab: anti-IL22

Front 38

IL-6, IL-21, BcL-6

Back 38

Dendritic Cells secrete IL-6 and IL-21 to Naive T-Cells, triggering their differentiation into Tfh CD4 Helper T Cells via Bcl-6 transcription factor expression.

Front 39

Tfh Cell Role and Purpose

Back 39

Critical Role in HUMORAL IMMUNITY.

Tfh CD4 Helper T Cells activate naive B-Cells to initiate antibody responses to infection, promoting antibody affinity, class switching, and Memory B Cell generation.

Front 40

IL-21 and CD40L

Back 40

Cytokines secreted by Tfh CD4 Helper T-Cells.

IL-21 -> B-Cell immunoglobin class switching.

CD40L -> Co-stimulates B-Cells.

Front 41

TGF-Beta and FoxP3

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TGF-Beta secreted by Dendritic Cells promotes Naive T-Cells to differentiate into Treg CD4 Helper T-Cells.

This is accomplished by FoxP3 transcription factor expression.

Front 42

Treg Cell Role and Purpose

Back 42

Treg CD4 Helper T-Cells main role is suppression of T/DC Cells and suppression of immune responses once pathogen is controlled.

Front 43

TGF-Beta and IL-10: Secreted by which T-Cell, for what purpose?

Back 43

Secreted by Treg CD4 Helper T-Cells. Act to immunosuppress antigen-specific T-Cells.

Front 44

CTLA-4 and CD25

Back 44

Both expressed on Treg CD4 Helper T-Celll surfaces.

CTLA-4 inhibits APCs by stripping B7s.

CD25 inhibits IL-2 by acting as an IL-2 sink, outcompeting.

Front 45

CD8+ (Cytotoxic) T-Cells: Purpose

Back 45

Release cytokines to induce apoptosis in Viral, Neoplastic, or intracellularly-infected host cells.

Front 46

CD8 T-Cell Functions: Perforin and Granzyme

Back 46

CD8 T-Cells can induce apoptosis by forming a pore on an infected cell with Perforin, allowing Granzyme Proteases to enter the pores and induce apoptosis via proteolytic cascade.

Front 47

CD8 T-Cell Functions: Fas Mechanism

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T-Cell surfaces express a ligand, FasL. This binds to Fas on MOST CELL SURFACES to activate proteolytic cascade -> apoptosis.

Front 48

CD8 T-Cell Functions: TNF-Alpha and Lethal Toxin

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Induce apoptosis, secreted by Cytotoxic CD8+ T-Cells.

Front 49

Severe Combined Immunodeficiency

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Greatly reduced or abolished T-Cell counts due to mutations in JAK3/IL-7Receptor/CD45. B and NK Cells are variably present depending on mutation.

Greatly increased susceptibility to viral, fungal, bacterial, and opportunistic infections.

Front 50

T-Cell Signaling Defects

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zap-70 and lck gene mutations.

Causes reduced, BUT NOT ABOLISHED, T-Cell signaling.

T-CELL COUNTS ARE NORMAL, but increased susceptibility to viral/fungal/bacterial/opportunistic infections.

Front 51

DiGeorge Syndrome

Back 51

Deletion of q22 gene -> no Tbx1 transcriptional factor to drive thymus organogenesis (and parathyroid/heart).

Ansent/defective/hypoplastic thymus at birth.

DRAMATICALLY REDUCED T-CELLS, greatly increased susceptibility to viral/fungal/bacterial/opportunistic infection.

Front 52

Acquired Immune Deficiency Syndrome (AIDS)

Back 52

Immune deficiency secondary to HIV, which decreases CD4+ Helper T-Cell counts.

When CD4+ cells drop below 200/mm3, patient has AIDS.

Marked by increasing incidence of cancers and susceptibility to oportunistic infections.

Front 53

Central Tolerance and AIRE

Back 53

Negative Selection during thymic development of T-Cells.

Causes deletion of T-Cells that have TCRs specific to self-antigens.

AIRE is the transcription factor that induces self-antigen/tissue-specific proteins to test T-Cells with.

Front 54

Peripheral Tolerance

Back 54

Tolerance mechanism OUTSIDE of thymus, in secondary immune organs (lymph nodes). Eliminates autoreactive T-Cells that dodged Central Tolerance.

Front 55

How does Peripheral Tolerance handle Autoreactive T-Cells?

Back 55

Tissues are sequestered behind barriers.

Treg Suppresses autoreactive T's with TGF-B and IL-10.

Fas/PD-L1 induces apoptosis.

Front 56

Attenuation: Fas

Back 56

T-Cells expressing Fas undergo apoptosis when bound to Activated T-Cell FasL in order to control immune response.

If FasL and Fas are on the same T-Cell, SUICIDE.

If FasL and Fas are o ndifferent T-Cells, FRATRICIDE.

Front 57

Attenuation: PD-1 and PD-1L

Back 57

PD-1 Ligand on Dendritic Cell binds to PD-1 on T-Cell, inducing apoptosis of the activated T-Cell to attenuate immune response.

Front 58

Attenuation: CTLA-4 and B7

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CTLA-4 binds to B7, blocking CD28 T-Cell Co-stimulation and inducing ANERGY of Naive T-Cells to reduce further immune response.

Front 59

Attenuation: Treg

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Treg IL-10/TGF-B secretion suppresses T-Cells.

Front 60

Attenuation: Cbl-B

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Promotes Ubiquitination of TCR and CD3, downregulating TCR expression.

Front 61

Autoimmune Lymphoproliferative Syndrome (ALPS)

Back 61

Fas/FasL deficiency, overproduction of Double Negative (CD4-CD8-) T-Cells due to no attenuation.

T and B Cell autoimmunity occurs, increased risk of hematological cancers.

DOES NOT CAUSE IMMUNODEFICIENCY.

Front 62

CAR-T Cell Therapy

Back 62

Genetically Engineered Chimeric Antigen Receptors (CARs).

Blood extracted from patient to get T-Cells, produce CAR-expressing T-Cells in lab, grow millions of them, infuse these CAR-T Cells into patient.

CAR-T Cells bind to cancer cells with higher affinity, killing them.

Front 63

Yescarta (Axicabtagene)

Back 63

CAR-T Therapy usedto treat Non-Hodgkin Lymphoma

Front 64

Immunologic Interventions: IFN-Alpha and Intron A

Back 64

Intron A contains Interferon-Alpha -> enhances NK/DC function to improve T-Cell activity and promote cancer cell death.

Front 65

Immunologic Interventions: IFN-Beta and Rebif Rebidose

Back 65

Multiple Sclerosis treatment.

Front 66

Immunologic Interventions: IL-2 and Proleukin

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IL-2 is a growth factor for NK and T-Cells, enhances cytotoxic reesponse against cancers.

Front 67

Immunologic Interventions: Checkpoint Inhibitors

Back 67

These are used for cancer treatment, block immune checkpoitn proteins PD-1 and CTLA-4 to BLOCK T-CELL SUPPRESSION.