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progenitor

In this phase I clinical trial, an antibody that recognizes CD28 with high affinity is injected into healthy volunteers to suppress the immune response for potential treatment of rheumatoid arthritis. CD28 is a critical co-stimulatory pathway involved in T cell activation, and targeting it may lead to therapeutic benefits.

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progenitor

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  1. progenitor Initial repertoire MHC-selected repertoire TCR a/b, CD4+ TCR a/b, CD8+ TCR a/b, TCR g/d Thymocyte development summary

  2. A functional T cell response requires recognition, proliferation and differentiation.

  3. Specific clones are present at low frequency within the naïve population. An effective immune response requires that reactive clones undergo rapid expansion - “clonal selection”.

  4. Activation of Naïve T cells An effective immune response requires that reactive clones undergo rapid expansion - “clonal selection”. Naïve CD4+ and CD8+ T cells must differentiate in order to provide effector functions. This limits the effector response to those T cell specificities that recognize an active pathogen infection.

  5. T lymphocytes circulate through lymph nodes where they can encounter antigen from a nearby infection

  6. If naïve T cells are presented with the appropriate antigen they will proliferate and differentiate

  7. T cells enter the lymph node through high endothelial venules using a multi-step process: L-selectin binding to vascular addressins, followed by chemokine-mediated integrin activation, binding to ICAM, and diapedesis. (Rolling, stopping, entry).

  8. CCR7 T cell homing to lymph nodes or to sites of infection is determined in part by the selective expression and activity of specific chemokines/chemokine receptors and adhesion molecules CX3CR3 CXCL10 CCL21

  9. Antigens may be brought to lymph nodes by dendritic cells which encounter pathogens in peripheral tissue and then migrate to local lymph nodes.

  10. Pathogens (and their antigens) can travel independently through the lymph and then be trapped by macrophages, or B cells, which are resident in the draining lymph node.

  11. T cells scan for specific antigen-bearing APCs using transient adhesion

  12. Recognition of antigen by the TCR leads to enhanced LFA-1 activity and stabilization of the T cell - APC interaction

  13. T cell APC Molecular rearrangements at the T cell - APC contact site generates an “immune synapse”

  14. Phosphorylation of the TCR on ITAMs initiates intracellular signals

  15. Protein tyrosine kinases couple the TCR to intracellular signaling pathways and the activation of transcription factors TCR CD4 CD28 PO4-Y- PO4-Y- -Y-PO4 -Y-PO4 Protein tyrosine kinases Phosphatidyl inositol pathway MAP kinase pathways Transcription factor activation

  16. Activity of the NFAT transcription factor is regulated by changes in the intracellular calcium level and function of the calcineurin phosphatase

  17. IL-2 production induces proliferation through an autocrine mechanism

  18. Immunosuppressants used to prevent transplant rejection act by blocking the production or function of Interleukin-2 Cyclosporin A and FK506 block TCR signals leading to NFAT activation and thereby block IL-2 synthesis. Rapamycin blocks signals from the IL-2 receptor

  19. Summary so far Naïve T cell activation occurs in secondary lymphoid tissue T cells use L-selectin, chemokine receptors and integrins to migrate into lymph nodes via HEV T cells scan for specific antigen on the surface of antigen presenting cells Stimulation of the TCR leads to establishment of a cell - cell complex: an “immune synapse” Signals from the TCR induce gene expression and proliferation Receptor clustering leads to receptor phosphorylation and activation of protein kinases Intracellular signaling pathways activate transcription factors, e.g. NFAT Expression of IL-2 and the high affinity IL-2 receptor is induced leading to proliferation

  20. Activation of naïve T cells requires a co-stimulatory signal provided by APCs Co-stimulatory signals are required for efficient production of IL-2: signals from the CD28 increase IL-2 gene transcription and the stability of IL-2 mRNA. Signals from CD28 also increase cell survival by antagonizing pro-apoptotic functions

  21. Antigen recognition in the absence of co-stimulation leads to tolerance Anergic cells cannot respond to subsequent stimulation, even if a co-stimulatory ligand is provided

  22. Co-stimulation is required for naïve T cell activation • Co-stimulatory signals are required for the production of IL-2. • Signals from CD28 increase cell survival by antagonizing pro-apoptotic functions • Stimulation through the TCR in the absence of co-stimulation leads to non-responsive state - “anergy”.

  23. You want to develop a treatment for rheumatoid arthritis. Focusing on the critical CD28 co-stimulatory pathway you generate an antibody which recognizes CD28 with high affinity and inject it into healthy volunteers as part of a phase I clinical trial. Why might CD28 be a particularly good target for suppression of an immune response? What do you think happens in the clinical trial? Nature 440 , 855-856 (13 April 2006)

  24. “Professional” antigen presenting cells Required for effective antigen presentation and activation of naïve T cells. Help define the conditions of T cell activation by expression of co-stimulatory ligands and cytokine production which determines the outcome T cell differentiation.

  25. Microbial products induce the expression of B7 co-stimulatory molecules on APCs

  26. Immature dendritic cells, such as Langerhans’ cells in the skin, take up antigen and transport it to regional lymph nodes. In the lymph node the dendritic cells mature, increasing expression of the B7 costimulatory molecule.

  27. Dendritic cells are dedicated APCs • Dendritic cells are highly phagocytic, but they lose this ability as they migrate to lymph nodes and mature. This allows them to provide a ‘snap-shot’ of antigens present in the tissue. • Mature dendritic cells express the DC-CK chemokine which attracts naïve T cells.

  28. Naïve CD4+ T cells have the potential to mature into different types of effector cells that secrete distinct sets of cytokines

  29. T reg Th17 TGFß IL-6 + TGFß CD4 APC IL-12 Th1 IL-4 Th2 Cytokines present during the activation of CD4 T cells help determine the outcome of differentiation

  30. The strength of the TCR signal can also influence the outcome of CD4 T cell differentiation

  31. Summary Naïve T cell activation occurs in secondary lymphoid tissue Signals from the TCR and co-stimulatory receptor induce gene expression and proliferation Co-stimulatory signals are critical for the activation of naïve T cells IL-2 production and cell survival is enhanced by co-stimulation Recognition of antigen in the absence of co-stimulation leads to anergy Professional antigen presenting cells dictate the outcome of naïve T cell activation Dendritic cells, macrophages, B cells have unique antigen presentation ability Elevation of MHC II and co-stimulatory ligands is dependent upon signals from pathogens Outcome of CD4 T cell differentiation is regulated by cytokines and antigen density

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