CD4 extra reading Flashcards
Th1 th2 and th17 homing patterns?
Th1, Th2, and Th17 cells have distinct patterns of homing, in large part because they express chemokine receptors and adhesion molecules that direct them to migrate into different sites of infections. We discussed the control of lymphocyte migration in Chapter 3 . Th1, but not Th2, cells express high levels of the chemokine receptors CXCR3 and CCR5, which bind to chemokines produced in tissues during innate immune responses. Therefore, Th1 cells tend to be abundant at sites of infection where the infectious agents trigger strong innate immune reactions; these agents include many bacteria and viruses. Th1 cells also express high levels of ligands for E-selectin and P-selectin, which assist in the migration of these cells to sites of strong inflammation (where the selectins are expressed on the endothelium). In contrast, Th2 cells express the chemokine receptors CCR3, CCR4, and CCR8, which recognize chemokines that are highly expressed at sites of helminthic infection or allergic reactions, particularly in mucosal tissues, and so Th2 cells tend to migrate to these tissues. Th17 cells express CCR6, which binds the chemokine CCL20, which is produced by various tissue cells and macrophages in some bacterial and fungal infections.
cd4 link to b cells?
the CD4 + helper T cells that remain in secondary lymphoid organs to help B lymphocytes are not classical Th1 or Th2 but Tfh cells that make some of the same cytokines that Th1 and Th2 cells do (see Chapter 12 ).
cytokine prod impact
This feature of T-cell subset development provides a powerful amplification mechanism. For instance, IFN-γ secreted by Th1 cells stimulates further Th1 differentiation and inhibits the generation of Th2 and Th17 cells. Similarly, IL-4 produced by Th2 cells promotes Th2 differentiation. Thus, once an immune response develops along one effector pathway, it becomes increasingly polarized in that direction, and the most extreme polarization is seen in chronic infections or upon chronic exposure to environmental antigens, when the immune stimulation is prolonged.
th1 differentiation driver?
The differentiation of antigen-activated CD4 + T cells to Th1 effectors is stimulated by many intracellular bacteria, such as Listeria and mycobacteria, and by some parasites, such as Leishmania, all of which infect DCs and macrophages. Th1 differentiation is also stimulated by viruses and by protein antigens administered with strong adjuvants.
All of these cytokines promote Th1 development; of these, IL-12 is probably the most potent. Many microbes stimulate NK cells to produce IFN-γ, which is itself a strong Th1-inducing cytokine and also acts on DCs and macrophages to induce more IL-12 secretion.
cd28 and b7?
The best characterized costimulatory pathway in T cell activation involves the T cell surface receptor CD28, which binds the costimulatory molecules B7-1 (CD80) and B7-2 (CD86) expressed on the surface of activated APCs.
B7-1 and B7-2 are structurally similar integral membrane single-chain glycoproteins, each with two extracellular immunoglobulin (Ig)-like domains. CD28 is a disulfide-linked homodimer, each subunit of which has a single extracellular Ig domain. Its cytoplasmic portion contains several tyrosine and proline residues that are involved in binding of adaptor and signaling proteins and in the delivery of activating signals (discussed later). CD28 is expressed on the vast majority of CD4 + T cells, but in adult humans, almost 50% of blood CD8 + T cells, mainly effector and memory cells, express little or no CD28.
The expression of B7 costimulators is increased by microbial products and the innate immune responses to infections, which ensures that T lymphocytes are activated only when needed. The B7 molecules are expressed mainly on APCs, including DCs, macrophages, and B lymphocytes. They are expressed at low levels on resting APCs and are induced by various stimuli, including microbial products that engage Toll-like receptors and cytokines such as interferon-γ (IFN-γ) produced during innate immune reactions to microbes. The induction of costimulators by microbes and by the cytokines of innate immunity promotes T cell responses to microbial antigens.
t cell surface molecule changes upon activation?
Changes in Surface Molecules During T Cell Activation
After activation by antigen recognition and costimulation, there are characteristic changes in the expression of various surface molecules in T cells ( Fig. 9.8 ) . Many of the molecules that are expressed in activated T cells are also involved in the functional responses of the cells.
- CD69. Within a few hours, T cells increase their expression of CD69. This protein binds to and reduces surface expression of the sphingosine-1 phosphate receptor 1 (S1PR1), which we described in Chapter 3 as a receptor that mediates egress of T cells from secondary lymphoid organs. The consequence of decreased S1PR1 expression is that activated T cells are retained in lymphoid organs long enough to receive the signals that initiate their proliferation and differentiation into effector and memory cells. After that occurs, CD69 expression decreases, the activated T cells reexpress high levels of S1PR1, and therefore the effector and memory cells can exit the lymphoid organs (see Chapter 3 ).
- CD25 (IL-2Rα). The expression of this component of the receptor for the growth factor interleukin-2 (IL-2) enables activated T cells to respond to this cytokine. This process is described later.
- CD40 ligand (CD40L, CD154). Within 24 to 48 hours after antigen recognition, CD4 + T cells express high levels of the ligand for CD40. The expression of CD40L enables these activated T cells to mediate their key effector functions, which are to help macrophages and B cells. In addition, as discussed earlier, CD40L on the T cells activates DCs to become better APCs, thus providing a positive feedback mechanism for amplifying T cell responses.
- CTLA-4 and PD-1. CTLA-4 is expressed on T cells within 24 to 48 hours after antigen recognition, and PD-1 may be induced even more rapidly. The role of these inhibitors in limiting immune responses is described later in this chapter, in self tolerance in Chapter 15 , and in tumor immunity in Chapter 18 .
- Adhesion molecules and chemokine receptors. During activation, T cells reduce expression of molecules that bring them to secondary lymphoid organs (such as L-selectin [CD62L] and the chemokine receptor CCR7) and increase the expression of molecules that are involved in their migration to peripheral sites of infection and tissue injury (such as the integrins LFA-1 and VLA-4, the ligands for E- and P-selectins, and various chemokine receptors). These molecules and their roles in T cell migration were described in Chapter 3 . Activation also increases the expression of CD44, a receptor for the extracellular matrix molecule hyaluronan. Binding of CD44 to its ligand helps retain effector T cells in the tissues at sites of infection and tissue damage.
