Immunology Week 7 Review

Immunology Week 7 Review  OBJECTIVES FROM 9/30 (IN SHIFTING LECTURES, SOME OF THESE GOT LEFT HERE EVEN THOUGH THEY WERE COVERED MORE 9/2)  Outline the major events that transform a hematopoietic stem cell into a mature, naïve T-cell  Identify proteins and receptors that aid in the deve...

Immunology Week 7 Review  OBJECTIVES FROM 9/30 (IN SHIFTING LECTURES, SOME OF THESE GOT LEFT HERE EVEN THOUGH THEY WERE COVERED MORE 9/2)  Outline the major events that transform a hematopoietic stem cell into a mature, naïve T-cell  Identify proteins and receptors that aid in the development & drive of hematopoietic stem cells  Describe steps & importance of Notch signaling  Describe the microenvironments of the thymus where each stage of T-cell development takes place  Describe the changes in expression of CD4, CD8, and TCR that occur during T-cell development  Compare & contrast αβ and γδ cells (& start familiarizing yourself with how they are similar/different to B1 & B2 cells- more of a focus next module)  Define and describe the importance of, and the basis for, positive and negative selection.  Describe the relationship between positive selection & MHC restriction, & the relationship between negative selection & central tolerance  Recognize the variety of T cells that are generated in the thymus and articulate a basic understanding of the events that lead to the development of each lineage, particularly the CD4+, CD8+ and δγ!  REVIEW OF LAST CLASS  Outline the major events that transform a hematopoietic stem cell into a mature, naïve T-cell (meaning it’s fully developed, gone through graduation, but it has not encountered its antigen yet)  Decreased PU.1 TF → common lymphoid progenitor (CLP) → IL-7 + expression of different cell surface markers (review these), making T cell Receptor, expressing co-receptors, etc. (e.g. CD2, CD5, CD4 & CD8, RAG)  Identify proteins and receptors that aid in the development & drive of hematopoietic stem cells  Notch  CD34  CD44  Describe steps of Notch signaling 1. Notch1 membrane-associated receptor on surface of thymocytes binds to its ligand (Notch1 Ligand) on thymic epithelium (sometimes called stromal cells of thymus) 2. Induces a protease to cleave intracellular domain of Notch1, releasing it from plasma membrane 3. Soluble intracellular domain is translocated to nucleus of thymocyte 4. Removes repressive transcription factors & recruits co-activating transcription factors 5. Turns on expression of genes essential for T-cell development  REVIEW OF LAST CLASS  Describe the microenvironments of the thymus where each stage of T-cell development takes place  This is actually better visualized in 10/2  Review why it’s critical they interact with thymic epithelial cells, where positive & negative selection, & the checkpoints occur.  T-cell progenitors enter from blood & migrate to subcapsular region 1. Proliferate & rearrange their T-cell receptor genes, leading to development of mature γδ cells & immature αβ T cells expressing a β chain & a pre-TCR 2. Cells move deeper into thymus for 2nd phase- Positive selection 3. 3rd phase- Negative selection 4. Thymocytes surviving positive & negative selection leave thymus as mature single-positive CD4 or CD8 T cells & enter circulation  REVIEW OF LAST CLASS  Describe the changes in expression of CD4, CD8, and TCR that occur during T-cell development  T cell progenitor starts out as double negative (CD4-CD8-), then becomes double positive (CD4+CD8+) after successful assembly of αβ receptor & commitment to αβ lineage, then cells become either CD4+ or CD8+ single positive after positive selection.  Compare & contrast αβ and γδ cells (& start familiarizing yourself with how they are similar/different to B1 & B2 cells- more of a focus next module)  B1 is similar to γδ while conventional B2 is similar to traditional αβ  REVIEW OF LAST CLASS  Define and describe the importance of, and the basis for, positive and negative selection.  Describe the relationship between positive selection & MHC restriction, & the relationship between negative selection & central tolerance  Positive selection- thymocytes that bind self-MHC/peptides in the cortex with intermediate affinity are selected to mature, migrating to the medulla for negative selection  During positive selection, interaction of the T-cell receptor with a peptide presented by MHC class II or MHC class I determines whether the T cell commits to the CD4 or the CD8 T-cell lineage  A T-cell receptor (TCR) that interacts with peptide:MHC class I complexes on a thymic epithelial cell becomes a single-positive CD8 thymocyte  A T-cell receptor that interacts with peptide:MHC class II complexes becomes a single-positive CD4 thymocyte  Negative selection- Thymocytes whose T Cell Receptors (TCRs) bind self-MHC/peptide complexes with too-high affinity are induced to die (apoptosis)  T cells with a T-cell receptor (TCR) that binds too tightly to self-MHC class I or self-MHC class II on antigen- presenting dendritic cells & other APCs in the thymus are signaled to die →→→  T cells with a receptor that binds moderately to self-MHC class I or self-MHC class II on dendritic cells, macrophages, & other cells in thymus are signaled to survive, mature, & enter peripheral circulation→→→ REVIEW OF LAST CLASS  Recognize the variety of T cells that are generated in the thymus and articulate a basic understanding of the events that lead to the development of each lineage, particularly the CD4+, CD8+ and δγ!  Review figure 7.7  OBJECTIVES FROM 10/2  Re-view dendritic cell maturation & antigen presentation  Describe the “homing” of T cells to secondary lymphoid tissues & lymphocyte trafficking  Define the immunological synapse & state its purpose  Describe T-cell signal transduction and what signals are needed?  Which activate? Which trigger anergy? Which trigger effector function?  What are ITAMs and what are their roles in the immunological synapse & signal transduction  Compare & contrast CD4+ & CD8+ Maturation  Identify the different sub-types of CD4+ cells, the roles of the five different subtypes we learned, and activation pathways (e.g. cytokines) that trigger the different responses REVIEW OF LAST CLASS  Re-view dendritic cell maturation & antigen presentation REVIEW OF LAST CLASS  Describe the “homing” of T cells to secondary lymphoid tissues & lymphocyte trafficking REVIEW OF LAST CLASS  Define the immunological synapse & state its purpose  The area of contact between a naive T cell & a dendritic cell forms an ordered structure that functions as an immunological synapse  Immunological synapse- structure formed when two immune-system cells bind to each other with multiple receptors & cell- adhesion molecules, where signals can be exchanged & effector molecules secreted  T cell-Dendritic cell immunological synapse is divided into the central supramolecular activation complex (c-SMAC) & the peripheral supramolecular activation complex (p-SMAC)  REVIEW OF LAST CLASS  Describe T-cell signal transduction and what signals are needed? 1. Antigen-specific signal (arrow 1) is delivered when TCR & CD4 co-receptor recognize p:MHC class II complex on dendritic cell 2. Co-stimulatory signal (arrow 2) is delivered when T-cell’s CD28 co-stimulatory receptor binds to B7 (CD80/86) co-stimulator on dendritic cell  Activation & clonal expansion of antigen-specific naive T cell occurs ONLY if antigen-specific AND co-stimulatory signals are delivered together  Which activate? Which trigger anergy? Which trigger effector function?  First signal only = tolerance/anergy  First + second signal = Activation  First +second signal +cytokines =effector function  REVIEW OF LAST CLASS  What are ITAMs and what are their roles in the immunological synapse & signal transduction  Immunoreceptor tyrosine-based activation motif (ITAM)- conserved sequence of four amino that is repeated twice in the cytoplasmic tails of the TCR & responsible for initiation of intracellular immune signaling and activation of immune cells  We didn’t fully cover this definition, but I wanted to include it here so it made more sense- as long as you know that it is what is responsible for initiating the intracellular signaling  Compare & contrast CD4+ & CD8+ Maturation & Activation  They mature the same way (see slide 4 & 7 above) but they split and become single positive during positive selection. After negative selection they are fully mature and allowed to leave the thymus. In differences in activation, they both still need the First + second signal = Activation  They just differ in other co-stimulatory molecules in the immunological synapse:  *CD40 & CD40L are fair game from this video (CD4)  *4-1BB & 4-1BBL are also fair game (CD8)  REVIEW OF LAST CLASS  Identify the different sub-types of CD4+ cells, the roles of the five different subtypes we learned, and activation pathways (e.g. cytokines) that trigger the different responses  OBJECTIVES FROM 10/4  Define the immunological synapse & state its purpose  Describe T-cell signal transduction and what signals are needed?  Which activate? Which trigger anergy? Which trigger effector function?  What are ITAMs and what are their roles in the immunological synapse & signal transduction  What is the importance & significance of IL-2?  Compare & contrast CD4+ & CD8+ Maturation  Identify the different sub-types of CD4+ cells, the roles of the five different subtypes we learned, and activation pathways (e.g. cytokines) that trigger the different responses (their effector functions)  Define the different co-stimulatory molecules & signals (& back-ups)  What is a memory T cell? REVIEW OF LAST CLASS (JUST COVERING THE NEW RED ONES)  What is the importance & significance of IL-2?  Proliferation and differentiation of activated naive T cells are driven by the cytokine interleukin-2 (IL-2) REVIEW OF LAST CLASS (JUST COVERING THE NEW RED ONES)  Identify the different sub-types of CD4+ cells, the roles of the five different subtypes we learned, and activation pathways (e.g. cytokines) that trigger the different responses (their effector functions)  REVIEW OF LAST CLASS  Define the different co-stimulatory molecules & signals (& back-ups)  CD28:CD80/86 (B7)  They also have other co-stimulatory molecule *CD40 & CD40L for CD4+ & 4-1BB & 4-1BBL for CD8  If the CD8 cell is missing CD28, CD58 can also stimulate CD8+ T cells  What is a memory T cell?  When T cells divide, it will split into 2- one effector and one memory  Memory T cells typically express CD28, increase their expression of some adhesion molecules but decrease their surface expression of L-selectin  By increasing their expression of CD28, memory T cells are more likely to respond rapidly to CD80/86 displayed by APC  By decreasing L-selectin expression, memory T cells no longer home to lymph nodes but home to sites of inflammation because of increased expression of other adhesion molecules  Memory T cells can be identified by CD45RO receptors, while active cells express CD45RA