CD4+ T Cells - Overview and Progress

CD4+ T Cells - Part I

• Brian Rudd is from the Department of Microbiology and Immunology at Cornell University.
• His contact information, including office hours are provided
• The covered text for the next three lectures is detailed. Callahan & Yates (Chapter 10), Parham #3 (pages 75-83, 212-245, 305-307, 311-315), and Abbas #7 (Chapters 9, 10, and 11) are all optional readings.

Overview of the Immune System

• The immune system is divided into innate and adaptive immunity.
• Innate immunity includes Physical barriers, PRR, macrophages, neutrophils, phagocytosis, killing, and NK cells.
• Adaptive immunity involves vaccines, MHC/TCR, CD4 T cells, dendritic cells, CD8 T cells, B cells, antibodies, and BCR.
• Malfunctions in the immune system can lead to chronic inflammation, hypersensitivity, immune deficiency, and autoimmunity.

Progress in Adaptive Immunotherapy for Cancer in Companion Animals

• This review discusses the progress in adaptive immunotherapy for cancer in companion animals with a goal of curing cancer.

Forest and Trees

• This slide shows an image of a forest with trees.

CD4+ T Cell Response

• The CD4+ T cell response has a typical activation, expansion, contraction, and maintenance cycle overtime.
• The response is seen from a population/individual cell level.

Learning Objectives

• The learning objectives for the course are based on the minimum knowledge needed to pass.
• They cover activating CD4+ T cells, molecular interactions, the role of IL-2, clonal expansion, and turning off T cell signaling.

Big Picture View of T Cell Activation

• This is a high-level overview of T-cell activation.

Back to the Basics

• Every T cell is unique and expresses a single type of T cell receptor (TCR).
• The TCR recognizes a specific peptide presented by an MHC molecule on another cell's surface.

The Immune System Generates a Diverse Repertoire of T Cells

• The diverse repertoire of T cells is generated through recombination/rearranging V-(D)-J germline segments by enzymes RAG1 and RAG2.
• Also involves the addition of N-nucleotides, and pairing different alpha and beta chains.

T Cells - by the Numbers

• The number of possible TCRs is very high (~10^15).
• This possibility is linked to size and thymic selection.
• Total T cells in a mouse are on the order of ~8 x 10^7, and significant amounts reside in lymph nodes, with ~5M in the blood.
• The number of CD4+ T cells specific for a peptide varies.
• Different individuals may respond to different or some of the peptides from a pathogen.

Very Few T Cells Are Specific for Any One Microbe

• The number of CD4+ T cells specific for a given peptide:MHCII molecule is low (1 in 2e5 to 2e6)

Key Question: How Do These Few T Cells Patrol All Tissues Where Antigen May Be Present?

• This focuses on the need to bring antigen and lymphocytes together in lymph nodes.

Antigen and Lymphocytes Must Be Brought Together in Lymph Nodes

• Dendritic cells take up antigens and migrate to lymph nodes.
• This helps bring the antigen and lymphocytes (T Cells) together in the lymph nodes needed for response

What Initiates Migration of Dendritic Cells to Lymph Nodes During Infection?

• Dendritic cells are immature in sites of infection and mature in lymph nodes.
• Immature DCs prioritize antigen uptake and are low in MHC, B7, and CCR7 expression. Mature DCs prioritize antigen presentation with high expression in MHC, B7, and CCR7.
• Immature DCs have high antigen uptake but mature DCs have low antigen uptake.

T Cell Migration

• Mature DCs enter lymph nodes via afferent lymphatics.
• Naive T cells enter the nodes via the blood and stay for ~2-24 hrs
• T cells that do not encounter specific antigen return to circulation.
• T cells that DO encounter specific antigen become activated, proliferate, and differentiate into effectors (~3 days).
• Dendritic cells in lymph nodes can contact up to ~5,000 naive T cells/hr

Live Cell Imaging of T Cells and DCs in a Lymph Node

• Live cell imaging shows how dendritic cells and T cells interact in the lymph node
• This is observed over time.

Key Question: How Do T Cells Know That It Is an Appropriate Time to Be Activated?

• This question explores the need for specific activation signals

T Cell Activation Requires Interactions with Other Cells

• T cells recognize antigens presented by MHC molecules on the surface of other cells.
• CD4+ T cells recognize peptides in the context of MHC class II molecules on cells like dendritic cells, B cells, and macrophages.

Activation of T Cells Requires 2 Signals

• T cell activation requires signal 1 (TCR/peptide) and signal 2 (CD28/B7)
• Professional APCs (Dendritic cells, macrophages, B cells) express both MHCII and co-stimulatory molecules (B7)
• Expression of CD80 and CD86 (which are B7 molecules) is upregulated during DC maturation. This is crucial for proper T cell activation

Possible Outcomes

• Outcomes for T cells are dependent on signals received. Single signal 1 leads to anergy; signal 1 plus signal 2 leads to activation.

How is the TCR Signal Transduced?

• TCRs recognize antigens, but need helper molecules (CD3) to transduce the signal.
• Antigen binding triggers phosphorylation cascades that activate intracellular signaling pathways and gene expression.

What Does the Co-receptor Do?

• CD4 co-receptor binds to MHC class II, increasing TCR affinity for MHC and lowering the threshold of activation.
• Co-receptor binding significantly reduces the number of MHC molecules needed for effective activation of naïve T cells

The Immunological Synapse

• The immune synapse is an area of close contact between two cells (e.g. T cell and antigen presenting cell).
• The outer ring involves adhesion molecules whilst the inner ring is where TCR/MHC, CD28/B7, interact.

Key Question: What Signals Are Required for T Cells to Start Proliferating?

• The key question explores how T cells know when to start and stop proliferating.
• This is linked to expansion, maintenance and contraction cycles

Proliferation Is Driven by IL-2

• Signal 1 and signal 2 are required for T cell activation
• IL-2 released by activated T cells binds to IL-2 receptors on T cells (autocrine growth factor), driving further proliferation.

Activated T Cells Produce and Respond to IL-2

• Activated T cells express the high-affinity IL-2 receptor, differing from naive T cells which only express the low-affinity receptor.
• This increased expression along with IL-2 production drives proliferation.
• IL-2 signaling is a target for many immunosuppressive drugs.

Activated T Cells Undergo Massive Clonal Expansion

• T cells rapidly proliferate (2-3 times per day)
• Individual precursor pools produce millions of effector cells in a week
• A significant percentage of effector cells can be highly specific for the same peptide:MHC complex.

How Do We Turn T Cell Proliferation Off?

• Cross-linking of CD28 delivers co-stimulation and then leads to CTLA-4 expression.
• CTLA-4 binds B7 more strongly than CD28, delivering inhibitory signals, downregulating IL-2 signaling, stopping proliferation, and inducing apoptosis.

Why Do I Need to Learn This Stuff?

• This section is focused on the motivation for learning this information.

Ipilimumab: CTLA-4 Inhibitor

• Ipilimumab is a CTLA-4 inhibitor.
• CTLA-4 is conserved in both dogs and humans.

Success! (Data on Ipilimumab)

• This section likely depicts results of studies using ipilimumab, illustrating its clinical effect or efficacy.

And the Nobel Prize Goes To...

• This section likely points out the researchers associated with a notable discovery related to T cell activation.

Summary

• Multiple key questions are posed in relation to T cell activation, antigen recognition, infection, and proliferation.