Where do lymphocytes go after leaving the bone marrow or thymus?
They circulate through blood to lymph to secondary lymphoid tissues (lymph nodes, spleen, mucosal tissues) to search for antigen
How do lymphocytes (especially T cells) travel through the body?
Blood → enter lymph nodes via HEVs → scan for antigen → exit via efferent lymphatics → return to blood via thoracic duct
What is lymphocyte recirculation?
Continuous movement of lymphocytes through blood, lymph nodes, lymph, and back to blood
What is the general time course of the T cell response?
0–6 hr antigen capture → 6–24 hr APC migration → 1–2 days T cell activation → 2–4 days proliferation → 4–7 days effector cells exit
How does antigen travel to lymph nodes?
Free antigen via lymph or dendritic cells carrying antigen
Which method is most important for T cell activation?
Dendritic cells carrying antigen
How do lymphocytes enter lymph nodes?
Through HEVs via rolling, activation, adhesion, and diapedesis
Where are T cells located in the lymph node?
Paracortex
Where are B cells located in the lymph node?
Follicles (cortex)
Where do APCs go in the lymph node?
Paracortex (T cell zone)
What is the fibroblastic reticular cell (FRC) network?
Structural scaffold that guides T cells and dendritic cells and distributes chemokines
What is S1P?
Lipid signaling molecule high in blood and lymph
What is S1PR1?
Receptor for S1P on lymphocytes
What is the function of S1P
S1PR1? / Controls lymphocyte exit from lymph nodes
How does S1P signaling work?
Cells follow S1P gradient (low in node → high in blood) to exit
What are the 3 signals required for T cell activation?
Signal 1 (antigen), Signal 2 (costimulation), Signal 3 (cytokines)
What molecules are involved in signal 1?
TCR, MHC, CD4 or CD8, CD3
What molecules are involved in signal 2?
CD28 (T cell) and B7/CD80/CD86 (APC)
What happens if signal 1 occurs without signal 2?
Anergy or apoptosis (peripheral tolerance)
What molecules are involved in signal 3?
Cytokines (IL-12, IL-4, TGF-β, IL-6)
What is paracrine signaling in T cell activation?
Cytokines from nearby APCs influence T cell differentiation
What is autocrine signaling in T cell activation?
T cells produce IL-2 to stimulate their own proliferation
What is IL-2’s role?
Drives T cell proliferation (clonal expansion)
What is the role of PAMP
PRR interactions? / Determines cytokines released → determines helper T cell type
What is the cSMAC?
Central region of immunological synapse with TCR and signaling molecules
What is the pSMAC?
Peripheral ring with adhesion molecules for stability
What is the function of CD3?
Transmits TCR signal inside the cell
What is the function of CD4?
Binds MHC II and strengthens signaling
What is the function of CD8?
Binds MHC I and supports cytotoxic activation
What is the function of CD28?
Provides costimulatory signal for activation
What is the function of CD40?
Activates APCs and helps B cells via CD40L interaction
What is the role of ITAMs?
Become phosphorylated and initiate signaling cascade
What is the role of LCK?
Tyrosine kinase that phosphorylates ITAMs and starts signaling
What are the outcomes of CD3 signaling?
Cytokine production, proliferation, differentiation
What transcription factors are activated?
NFAT, NF-κB, AP-1
What is CTLA-4?
Inhibitory receptor that blocks T cell activation
How does CTLA-4 work?
Competes with CD28 for B7 and shuts down activation
What is a checkpoint inhibitor?
Drug that blocks inhibitory signals (CTLA-4, PD-1)
What is the effect of checkpoint inhibitors?
Enhances T cell response against cancer
What side effects occur with checkpoint inhibitors?
Autoimmune-like effects (rash, colitis, hepatitis, etc.)
What are intracellular signaling events of T cell polarization?
Cytokines → JAK-STAT → transcription factors → differentiation
What do Th1 cells do?
Activate macrophages and fight intracellular pathogens
What diseases are associated with Th1?
Autoimmunity and chronic inflammation
What do Th2 cells do?
Activate eosinophils, promote IgE, fight parasites
What diseases are associated with Th2?
Allergies and asthma
What do Th17 cells do?
Recruit neutrophils, fight extracellular bacteria/fungi
What diseases are associated with Th17?
Autoimmune and inflammatory disorders
What do Treg cells do?
Suppress immune responses and maintain tolerance
What happens if Tregs are too low or too high?
Low → autoimmunity, High → cancer immune suppression
What is a Treg?
CD4+ T cell that suppresses immune responses
What is the difference between central and peripheral Tregs?
Central = thymus-derived, Peripheral = induced in tissues
What is the phenotype of Tregs?
CD4+, CD25+, FOXP3+, CTLA-4
How do Tregs suppress immune responses?
IL-10, TGF-β, consume IL-2, inhibit APCs, suppress T cells
What defines a helper T cell subset?
Polarizing cytokines, master transcription factor, effector cytokines
What is T cell polarization?
Naïve T cell differentiates into specific helper subtype
What is reciprocal inhibition?
Helper T cell subsets suppress each other
What is T cell plasticity?
Ability of T cells to change phenotype
How do plasticity and reciprocal inhibition coexist?
Early flexibility, later commitment
What cells do helper T cells help?
Macrophages, B cells, CD8 T cells, other immune cells
How do T cells activate macrophages?
IFNγ secretion and CD40–CD40L interaction
What is the role of MHC class II?
Presents antigen to CD4 T cells
What is the role of IFNγ?
Activates macrophages and enhances killing
What is the role of CD40
CD40L? / Strengthens macrophage activation
What happens when macrophages are activated?
Increased killing, ROS production, cytokine release, better antigen presentation
What is macrophage polarization?
Differentiation into M1 or M2 states
What do M1 macrophages do?
Inflammation and pathogen killing
What do M2 macrophages do?
Tissue repair and anti-inflammatory functions
How do T cells influence macrophage polarization?
Th1 → M1, Th2 → M2
What is the relationship between T cells and macrophages?
Feedback loop where macrophages activate T cells and T cells activate macrophages