13. activation of naive t lymphocytes

where does T-cell activation occur?

• localized infection → draining/local lymph node

• systemic infection → spleen (+ lymph nodes)

how is dendritic cell migration directed to the paracortex?

chemokines CCL19 and CCL21 (produced in the paracortex)

CCR7

receptor for chemokines (CCL19 & CCL21) expressed by activated dendritic cells

what 3 things are required for initiation of T-cell responses?

• specific antigen recognition

• stable adhesion of T cells to APCs

• transduction of activation signals

what is the two signal model of naive T-cell activation?

activation of naive T cells requires simultaneous delivery of antigen specific and costimulatory signals

accessory molecules

T cell surface receptors that are not involved in antigen recognition

• signal transduction

• adhesion

note: T-cell receptor (TCR) is not capable of signal transduction

T-cell co-receptors

• CD4/CD8

• function with T-cell receptors (TCR) in antigen recognition and signal transduction

what provides the initiating or first signal for T-cell activation?

TCR and CD4/CD8 co-receptor together recognizing peptide-MHC complexes on APCs

what makes up the TCR (T-cell receptor) complex?

TCR, CD3, and ζ (zeta chain)

what is the function of CD3 & ζ (zeta chain)?

signal transduction

how are integrins involved in T cell activation?

• expressed on T cells

• mediate stable/strong adhesion between T cells and APCs

• switch from low-affinity state to high-affinity state when antigen recognition occurs between APCs and T cells + clustering

how is the co-stimulatory signal produced?

• CD28 (on T cells) binds to co-stimulatory B7 molecules expressed on professional APCs

• mature DCs initiate activation of naive T cells

• activation of APCs by microbes/innate immune response increases expression of costimulators

what happens if there is no co-stimulation signal?

the T cell either has no response or becomes tolerant (self-antigens)

• “resting” (co-stimulator deficient) APCs:

  • presenting self-antigen

  • immature (not activated)

  • no inflammation/infection

• → T cell responds to microbial antigens but not self antigens

how does co-stimulation affect T-cells?

• necessary for production & secretion of IL2 → autocrine signaling

• T cells start expressing high affinity IL2-R (receptor)

  • (at rest, express low affinity IL2-R)

what is IL2?

a growth factor/cytokine that drives T cell proliferation

CD4 T-cell independent activation of CD8 T-cells

microbes infect dendritic cells

CD4 T-cell dependent activation of CD8 T-cells

microbes do not infect dendritic cells (ex. viral infection, tumor cells)

• cross-presentation → one DC can present to both CD4+ and CD8+ T cells

  • activated CD4+ T cell produces cytokines that act on CD8+ T cells

how do certain adjuvants enhance immunogenicity of antigens?

use innate immunity (PRR signaling and inflammation) to activate APCs → express costimulatory molecules (B7)

what are the T cell co-inhibitory receptors?

• CTLA-4

• PD-1

when are the inhibitory receptors expressed?

when T cells become activated → function to inhibit activation (brakes)

how does CTLA-4 inhibit activation?

• interacts with B7 molecules on APCs

• has a higher affinity for B molecules → outcompetes CD28 (activator)

what does PD-1 interact with?

PD-L1/2 on APCs (→ inhibitory signal)

how are co-inhibitory receptors relevant to cancer treatment/treatment of persistent infections?

• drugs can have anti PD-1 / anti CTLA-4 effects

• remove T cell inhibition → allow T cell to kill tumor cell

• controlled autoimmunity

how do superantigens interact with T cells?

• cause uncontrolled, nonspecific activation of T cells

• ↑↑ T cell activation → lethal shock