This interaction and the resulting activating signals also involve a variety of accessory molecules on the Th cell and APC.
Following interaction of Th cells with antigen, numerous genes are activated:
immediate genes: within 1/2 hour of antigen recognition
variety of transcription factors: NF-AT, NF-kB, c-Fos, c-Myc, c-Jun.
early genes: within 1-2 hours
cytokine and cytokine receptor genes such as IL-2 and the high affinity receptor for IL-2 (IL-2R)
late genes: more than 2 days after
various adhesion molecule genes
Very Complex Signal Transduction Pathways - Beyond Scope of This Course
THE CO-STIMULATORY SIGNAL
Interaction of TcR with peptide+ MHC not sufficient for full activation of T cells. Widely accepted that naive T cells require 2 distinct signals for activation and subsequent proliferation into effector cells.
*The initial signal generated by the tri-molecular complex
*A subsequent antigen-non-specific co-stimulatory signal provided by interactions between CD28 on the T cell and B7 on the APC. B7 exists in two forms which are termed B7-1 and B7-2.
B7 is expressed constitutively on dendritic cells and on activated Macrophages and B lymphocytes.
CD28 expessed on both resting and activated T cells, while the other ligand for B7 (CTLA-4) is expressed on T cells only following activation but has a 20X greater affinity for B7.
In addition, CTLA-4 is present in much lower numbers on the cell surface than CD28. While the interaction between CD28 and B7 is an activation signal, the interaction between CTLA-4 and B7 is probably an inhibitory signal which prevents further activation of the T cell. CTLA-4 gene knock out mice which totally lack the ability to synthesize CTLA-4 suffer from lymphoproliferative disease.
CLONAL EXPANSION Vs. CLONAL ANERGY
Anergy is a state of inactivation marked by the inability of the cells to proliferate. Whether clonal anergy or clonal expansion occurs is determined by the absence or presence of a co-stimulatory signal. If a resting Th cell receives the TcR mediated signal in the absence of the co-stimulatory signal, then the Th cell will become anergic.
Once encountering antigen (as discussed above), the naive T cell enlarges into a blast cell and begins undergoing repeated rounds of cell division [CLONAL EXPANSION]. This transition takes ~ 48 hours. Secretion of IL-2 (or IL-4) and subsequent binding to respective receptors induces proliferation and differentiation. 2-3 divisions per day for 4-5 days. This large clone of cells differentiates into memory or effector T cell populations.
Activated CD4+ Tcells (participate in cytokine secretion and B cell help)
These cells form two subpopulations[Th1 and Th2] characterized by the panel of cytokines that they secrete. These two subpopulations are indistinguishable in terms of cell surface molecules
Th1
secrete IL-2, IFN-gamma, and TNF-beta
responsible for classic cell-mediated functions such as DTH [delayed type hypersensitivity] and activation of CD8+ Tcells
Th2
IL-4, IL-5, IL-6, IL-10
functions more effectively as a helper cell for B cell activation and antibody secretion
An additional effector cell, the activated CD8+ T cells (exhibit cytotoxic killing activity) and are commonly designated as CTL cells. We will talk about the activation/function of these cells in a later lecture.
Memory T cells
Long regarded as long lived antigen-activated T cells that respond with heightened activity to a subsequent challenge with the same antigen----->secondary reponse.?? Is this dogma changing??
Interesting point to be resolved: Some investigators have proposed that naive T cells have to be activated by dendritic cells while memory T cells can be activated by B cells and Macrophages.
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