Chapter 9: T Cell-Mediated Immunity Flashcards
What do secondary lymphoid structures do?
- Facilitate interaction of circulating T and B lymphocytes with antigen
- Makes surveilling entire body possible because antigen must be transported to secondary lymphoid to encounter naïve lymphocyte
(3)
What does the spleen do? Where do circulating pathogens delivered? What are periarteriolar lymphoid sheath (PALS) or follicles?
- Specialized to capture antigens that enter bloodstream
- Circulating antigens, B and T cells are delivered to marginal sinus
- Rich in dendritic cells, macrophages and marginal
zone B cells
- Rich in dendritic cells, macrophages and marginal
- T and B cells leave marginal sinus and travel to PALS or follicle
- Reticular fibroblast makes chemokines (CCL 19TH,21) to attract T cell (CCR7) from the sinus
- Follicular dendritic cells make chemokines CCL 13TH to attract B cell (CXCR5) from sinus
How do antigens enter the lymph node? How do B and T cells enter?
- Antigens enter via afferent lymph vessels in subcapsular sinus
- Lined by phagocytes that trap free antigen/pathogens
- T and B cell enter via small blood vessel High endothelial venules (HEVs)
How are antigens transported to peyer’s patch? Where do B and T cells enter? What do dendritic cells in peyer’s patch do?
- Antigens transported from lumen via microfold cells (M cells)
- T and B cells enter via HEVs
- Antigen-loaded dendritic cells are surveyed by T cells in T cell zone, If antigen is unrecognized it will be transported to mesenteric lymph node for further surveying
Describe the recirculation of T cells through lymph vessels.
- A T cell starts at lymphatic capillaries and makes its way through afferent LVs. Afferent lymph vessels to lymph nodes where it can encounter an antigen presenting cell. T cell will travel through efferent lymph vessels through a series of lymph nodes until it reaches the Thoracic duct. After the Thoracic duct T cells will enter circulation to reach tissue and continue to cycle through. (7)
How is the development of secondary lymphoid tissue initiated?
- Initiation by lymphoid tissue inducer cells and cytokines of the tumor necrosis factor family
How does T cell entry to lymphoid tissue occur? What is it similar to?
- Entry is mediated by the sequential actions of adhesion molecules and chemokine receptors
- Similar to recruitment of leukocyte to inflamed tissue (9)
Do all tissue use the same adhesion molecules?
- No, different tissues use different adhesion molecules
- CCL19, CCL21, CCR7, L-selectin, Integrins
Describe the motility of T cells. What is in the surfaces of sinusoid-like spaces? How are follicular dendritic cells networks similar?
- Highly motile within T-cell zone to survey dendritic cells for cognate antigens
- Surface of sinusoid-like spaced decorated with CCL19 and CCL21
- Chemokines used to help transport T cells and attract dendritic cells
- Similar network formed by FDCs in B cell follicles and is decorated with B cell chemoattractant CXCL13
What do FRCs do?
- Produce extracellular matrix that forms a meshwork(conduit) in T cell zone
What happens if a naive T cell recognizes a specific antigen on the surface of an activated dendritic cell?
- Its locomotion is arrested and it is retained in the T cell zone
- Proliferation for several days = effector T cells and memory cells
- Most effector T cells exit the lymphoid organ and reenter the bloodstream to site of infection
- Others migrate to B cell zone where they participate in germinal center response to help make antibodies
Explain how T cell screening is very efficient. Outline the motility, density, surface area, TCR, and circulation rate is related.
- Each T cell has a high probability of encountering antigen anywhere in the body
- High motility of T cells, 2 cell diameters per minute
- High density of T cells and recruitment of dendritic cells in T cell zone
- Large SA of dendritic for MHC complexes and contact
- TCR is very sensitive to antigen, one peptide can be enough to activate MHC and some T cells
- High rates of circulation if T cell does not encounter its antigen
How many dendritic cells does a T cell encounter in an hour?
- 100 per hour
- Local inflammation stimulates marked increase in influx and decrease efflux of lymphocytes into and out of lymph node contributing to node swelling
How is the exit of T cells from the T cell zone controlled? What role do S1P and S1P lyase play in this?
- Exit is controlled by chemotactic lipid (sphingosine-1-phosphate) S1P
- There is a gradient bt T cell zone and lymph. S1P made by epithelial cells lining lymph vessels, lyase made by lymphatic tissue
- S1PR1 (receptor)
- Low levels on surface of naive T cells that recently entered T cell zone
- If S1PR1 does not recognize antigen, upregulated = directs cell into cortical sinus = into efferent lymphatic vessel
- Activated T cell upregulated CD69 = S1PR1 internalized. Eventually CD69 will fade and S1PR1 will reexpress
What MHC molecules is antigen presenting? What are the three major APCs?
- MHC II
- Dendritic cells, macrophages, B cells
What are the two major classes of dendritic cells?
- Plasmacytoid dendritic cells
- Sentinels for viral infections, produced by T1 interferons
- Conventional dendritic cells
- Present antigen to T cell, found in nonlymphoidal tissue particularly at barrier tissue sites (NLT)
- Lymphoid tissue found in T cell zone of secondary lymphoid tissue (LT)
What happens when a conventional dendritic cell activates?
- The maturation is stimulated and migration to T cell zone to induce naive T cell activation
Immature cDC
- Low expression of co-stimulatory molecules and cannot activate naive T cell
- Actively phagocytic
Mature cDC
- High expression of co-stimulatory and MHC molecules can activate t cells
- Non-phagocytic
What routes of antigen processing and presentation are possible by dendritic cells?
- Receptor mediated phagocytosis, Macropinocytosis, viral infections, cross presentation after phagocytic or macropinocytic uptake, transfer from incoming dendritic a cell to resident Dendritic cell
- Different responses vary on viruses, bacteria, or fungi
What is the purpose of having subsets of conventional dendritic cells?
- Some are specialized for different modes of antigen presentation
- cDC1- T1 conventional dendritic cell
- Specialized for activating/priming naive CD8 T cells
- cDC2 - T2 conventional dendritic cells
- Specialized for activating/priming CD4 T cells
What are Monocyte-derived DCs? WHat are Langerhans cell?
- MoDCs take up antigen and diliver it to T cell zones
- Transfer antigen to LT-resident cDCs
- Specialized macrophages that reside in epidermis
- no cDCs in skin
- Take up antigen and transfer it to LT resident cDCs
How can MHC molecules and TCRs interact?
- Transient binding of T cells to dendritic cells
- Transient adhesion interactions are stabilized by specific antigen recognition
What type of signals can be delivered from cDCs to activate naive T cells?
- Interactions bt TCR/coreceptor and MHC:peptide complex, essential for activation
- Co-stimulatory signals, essential for Proliferation and survival
- Cytokines, essential for directing differentiation
What preparations occur when a T cell is activated?
- Induces metabolism to prep for rapid clonal expansion and differentiation
- Naive T cells have condensed chromatin arrested in G0
- Within hours of activation, the cell will undergo metabolic shift and change in morphology to prep for cell division
What is occurring in this image?
- Naive T cells is being activated by TCR and CD-28 mediated signaling leading to waves of signaling proteins leading to gene expression and cell cycle progression and clonal expansion
What happens to T cells after antigens are cleared?
- Most will be cleared via apoptosis (clonal contraction)
- 5-10% remain as memory T cells
What does the rapid expression of IL-2 result in? What Cytokines respond?
- Allow for the activation of T cells to respond to cytokines
- IL-2R
- IL-2RB/CD122, IL-2R lambdaC/CD132, IL-2Ra/CD25
What does IL-2 promote? What do Treg cells do?
- Promotes proliferation and differentiation However it more importantly generates and maintains Treg cells
- Mice without IL-2 have uncontrolled T cell proliferation and autoimmunity
- Treg cells cannot produce IL-2 and produce IL-2Ra
- take up most IL-2 until activated T cells express IL-2Ra
How are IL-2 and IL-2Ra induced in activated T cells?
- Secretion and expression are deferentially induced
- Based on TCR signal strength
- IL-2 Produced by one cell binds to high affinity IL-2 receptor of different T cells (paracrine)
What happens with receptors when T cell activation occurs? Why does this occur
- Inhibitory and co-stimulatory receptors are engaged to control clonal expansion and contraction
- CD80 and CD86 are important costimulatory molecules on APCs that bind to CD28 on T cells
What does CTLA-4 do? What can activate NFkB pathway?
- Inhibitory receptor for B7 molecule
- Multiple members of the TNF-TNFR superfamily can activate the pathway to sustain T-cell response
What happens to proliferating T cells?
- Differentiate into effector T cells programmed for altered tissue homing and loss of requirement for costimulation to act
- Cells presenting antigen on MHC may not express costimulatory molecule
What type of cell surface molecules are found on naive vs effector cells?
- TCR, L-selectin, CCR7, LFA-1, CD45RO
How can CD8 T cell be activated?
- Will become cytotoxic effector cell
- Can take up cDC1
- APC stimulation to induce expression of CD40L and IL-2 which cascade leading to production of IL-12
WHat subsets do CD4 T cells differentiate into? What are the two pathways of Treg development?
- TH1, TH2, TH17 are called non-TFH cells
- Positive selection in thymus
- Naive CD4 T cells develop into Treg in peripheral lymphoid organs (pTreg)
What role do cytokinesplay in the differentiation of CD4 T cells?
- Antigen presenting cells (mainly dedritic) and other innate immune cell can provide cytokines to induce naive CD4 development
What are TFH cells and how do they develop with respect to CD4 T-cells?
- Effector CD4 T cell subsets develop in concert
- TFH cells can produce Cytokines that influence isotype class-switching
- Primarily produce IL-21 which is important for optimal production of high-affinity, class-switched antibodies
- Helps antigen activated B cells develop into effector cells of different isotypes
What transcription factor is important for TFH development? What happens to naive T cells that produce IL-2?
- BCL-6 is important for TFH development. Expresses chemokines receptor CXCR5 which is essential for TFH localization in follicles
- Naive T cells that produce IL-2 become TFH cells while those that do not become non-TFH cells
- IL-2 Induces expression of tf BLIMP-1 which represses BCL-6
When do peripheral Treg cells develop? How do mucosal surfaces maintain tolerance for microbiota? What happens to a naive T cell in the presence of IL-6?
- Naive t cells are activated in the presence of TGF-beta and IL-2 (produced by dendritic cells)
- All-trans-retinoic acid (at-RA) binds to RA receptor (RAR) on T cell
- IL-6 and proinflammatory Cytokines are absent
- Development of pTreg maintains tolerance of microbiota
- In presence of IL-6 naive T cell will develop into Th17 cell
- Occurs when dendritic cell senses the antigen through TLR
- microbiota or pathogen penetrate epithelial barrier
How can CD4 T cell subsets be regulated?
- Subsets cross regulate each other’s differentiation through Cytokines production
- For immune response to be controlled efficiently, coordinated effector response must be orchestrated by one dominant subset
How can a T cell ensure it releases its effector molecules correctly?
- A synapse can form between the T cell and target to direct the release of the effector molecules
How are the effector functions of T cells determined?
- Determined by the array of effector molecules they produce, which can act locally or at a distance
How can cytotoxic T cells induce target cells to undergo programmed cell death?
Extrinsic (death receptor)
- Activated by FAS ligand (FasL)
- Formation of the death-inducing signaling complex(DISC)
Intrinsic
- Activated by the cytotoxic granules
- Formation of the apoptosome
What are the three major proteins in the granules of CD8 T cells? Why is apoptosis the preferential method of killing infected cells?
- Perforin - helps deliver contents of granule into cytoplasm of target cell
- Granzymes - serine proteases activate apoptosis when inside cytoplasm of target cell
- Granulysin - has antimicrobial action to induce apoptosis
How do T cells recognize their target and not harm other cells?
- Effector molecules are released from cytotoxic granules of a cytotoxic T lymphocyte in a highly polar way to prevent spillover to nearby cells
What else can cytotoxic T cells release?
- Cytokines IFN-gamma, TNF-a, LT-a all contribute to host defense
