Chapter 11: T-Cell Activation, Differentiation, and Memory
Which of the following conditions would lead to T-cell anergy? a. A naïve T-cell interaction with a dendritic cell in the presence of CTLA-4 Ig. b. A naïve T cell stimulated with antibodies that bind both the TCR and CD28. c. A naïve T cell stimulated with antibodies that bind only the TCR. d. A naïve T cell stimulated with antibodies that bind only CD28.
(a) Anergy. Signal 1 (if TCR is engaged) without costimulatory Signal 2 because CTLA-4 Ig will block the ability of CD28 to bind CD80/86). (b) No anergy. Signal 1 and Signal 2 are both generated. (c) Anergy. Signal 1 without Signal 2. (d) No anergy, but no activation either. Neither Signal 1 nor Signal 2 is generated.
The following sentences are all false. Identify the error(s) and correct. a. Macrophages activate naïve T cells better than dendritic cells. b. ICOS enhances T-cell activation and is called a negative coreceptor. c. Virtually all cells in the body express costimulatory ligands. d. CD28 is the only costimulatory receptor that binds to B7 family members. e. Signal 3 is provided by negative costimulatory receptors. f. Toxic shock syndrome is an example of an autoimmune disease. g. Superantigens mimic TCR-MHC class I interactions. h. CD4+ T cells interact with MHC class I on CD8+ T cells. i. Naïve T cells produce IFN-gamma. j. T-bet and GATA-3 are eff ector cytokines. k. Polarizing cytokines are only produced by APCs. l. Bcl-6 is involved in the delivery of costimulatory signals. m. TH17 and TFH cell subsets are the major sources of B-cell help. n. iTREG cells enhance inflammatory disease. o. Effector cytokines act exclusively on T cells. p. Central memory T cells tend to reside in the site of infection. q. Like naïve T cells, effector memory cells express CCR7
(a) Dendritic cells are best at activating naïve T cells— they express a high density of costimulatory ligands and MHC molecules. (b) ICOS is a positive costimulatory receptor (it is expressed on some effector T cells, including TFH cells). (c) Most cells do not express costimulatory ligands. Professional APCs (and thymic epithelial cells) are among the only cells that do. (d) ICOS and CTLA-4 also bind B7 family members (CD80 and CD86). PD1 also binds a B7 like molecule, PD-L1. (e) Signal 3 is provided by cytokines, which include the polarizing cytokines that induce helper T-cell lineage differentiation. (f) It is a disease caused by T-cell response to superantigens (bacterial and/or viral), not autoantigens. (g) They mimic some TCR-MHC class II interactions. (h) They do not have any receptor for MHC class I and do not interact directly with CD8 T cells via their TCRs, which bind to MHC class II. (i) Naïve T cells do not produce any eff ector cytokines. (j) They are master transcriptional regulators of T helper cell lineage differentiation. (k) APCs can make some polarizing cytokines, but many of these cytokines originate from other cells, including other T cells, B cells, mast cells, and NK cells. (l) T-bet is a master transcriptional regulator of TFH lineage differentiation. (m) TFH and TH2 are classically the major sources of B-cell help, although all helper subsets can interact with B cells and influence Ig class switching. (n) They inhibit T-cell activation. (o) Effector cytokines have many different cellular targets, including B cells, endothelial cells, stromal cells in tissues, innate immune cells, and so on, as well as other T cells. (p) Central memory cells tend to reside in secondary lymphoid organs. (q) CCR7 attracts cells to secondary lymphoid tissue, and effector cells tend to rove the periphery. They typically downregulate CCR7.
Like TH1 and TH2 cells, TH17 and TREG cells cross-regulate each other. Which of these two statements about this crossregulation is (are) true? Correct either, if false. a. TGF-beta is a polarizing cytokine that stimulates upregulation of each of the master transcriptional regulators that polarize T cells to the TH17 and TREG lineages. b. IL-6 inhibits polarization to the TREG lineage by inhibiting expression of ROR gamma.
(a) True. It stimulates production of both FoxP3 and ROR gamma. (b) False. IL-6 in combination with TGF-beta polarizes cells to the TH17 lineage, an event that requires ROR gamma. IL-6 acts in part by inhibiting expression of FoxP3.
A virus enters a cut in the skin of a mouse and infects dendritic cells, stimulating a variety of PRRs both on and within dendritic cells that induce it to produce IL-12. The mouse subsequently mounts an immune response that successfully clears the infection. Which of the following statements is(are) likely to be true about the immune response that occurred? Correct any that are false. a. The infected dendritic cells up-regulated CD80/CD86 and MHC class II. b. The dendritic cells encountered and activated naïve T cells in the skin of the mouse. c. Naïve T cells activated by these dendritic cells generated signals that released internal Ca2+ stores. d. Naïve T cells activated by these dendritic cells were polarized to the TH2 lineage. e. Only effector memory T cells were made in this mouse.
(a) Very likely. Any activated professional APC, like a dendritic cell, up-regulates MHC molecules and costimulatory ligands, making them ideal activators of T cells. (b) Very unlikely. Activated dendritic cells travel to the draining lymph nodes (or spleen) and encounter naïve T cells there, not in peripheral tissues. Naïve T cells travel among secondary lymphoid organs, not peripheral tissues. However, eff ector T cells and some memory T cells, do travel to peripheral tissues and can be activated by dendritic cells there. (c) Very likely. TCR stimulation rapidly induces Ca2+ mobilization. (d) Very unlikely. The virus induced dendritic cells to make IL-12, one of the central polarizing cytokines for the TH1 lineage. (e) Very unlikely. Central memory cells were certainly generated, too.
Your lab acquires mice that do not have the GATA-3 gene (GATA-3 knockout mice). You discover that this mouse has a difficult time clearing helminth (worm) infections. Why might this be?
A mouse without GATA-3, the master regulator for TH2 lineage commitment, will be unable to generate TH2 cells, which are instrumental in mounting the immune response to worm infections. TH2 cells help B cells to produce IgE, which has potent anti-parasite activity.
You isolate naïve T cells from your own blood and want to polarize them to the TH1 lineage in vitro. You can use any of the following reagents to do this. Which would you choose? Anti-TCR antibody CTLA-4 Ig IL-12 IL-4 anti-CD80 antibody IL-17 IFN gamma anti-CD28 antibody
You will need to supply Signal 1 (anti-TCR), Signal 2 (anti-CD28), and Signal 3 (IL-12). CTLA-4 Ig and anti-CD80 both bind to the ligands for the costimulatory receptors and would not engage your T cells.
A new effector T-cell subset, TH9, has been recently identified. It secretes IL-9 and IL-10 and appears to play a role in the protection against intestinal worm infection. What other information about this subset would help you to determine if it should be considered an independent helper T-cell lineage?
Your discussion should include a recognition of the three properties that distinguish T helper lineages: a unique set of polarizing cytokines, a unique master gene regulator, and a unique set of effector cytokines. Knowing which cytokines polarize a naïve T cell to this lineage as well as the identity of a unique master regulator that induces TH9 lineage differentiation would strengthen the case for placing this in a unique T lineage category. Knowing how stable the phenotype is would also be useful. Does it differentiate into other subsets, or is it stable in effector function and phenotype? Th is property would not preclude TH9 from being considered a distinct lineage (e.g., recall that TH17 and TREG cells can give rise to other lineages) but would add complexity to your assessment.