Molecular Biology of the Cell

Bruce Alberts, Alexander Johnson, Julian Lewis

Chapter 24

The Innate and Adaptive Immune Systems - all with Video Answers

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Chapter Questions

Problem 1

T cells whose receptors strongly bind a self-peptide-MHC complex are killed off in peripheral lymphoid organs when they encounter the self peptide on an antigen-presenting dendritic cell.

Eric Goldman

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Problem 2

To guarantee that the antigen-presenting cells in the thymus will display a complete repertoire of self peptides to allow elimination of self-reactive T cells, the thymus recruits dendritic cells from all over the body.

Eric Goldman

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Problem 3

The antibody diversity created by the combinatorial joining of $\mathrm{V}, \mathrm{D},$ and $\mathrm{J}$ segments by $\mathrm{V}(\mathrm{D})$ J recombination pales in comparison to the enormous diversity created by the random gain and loss of nucleotides at $V$, D, and J joining sites.

Eric Goldman

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Problem 4

Why do living trees not rot? Redwood trees, for example, can live for centuries, but once they die they decay fairly quickly. What might this suggest?

Patsy Naomi

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Problem 5

It would be disastrous if a complement attack were not confined to the surface of the pathogen that is the target of the attack. Yet, the proteolytic cascade involved in the attack liberates biologically active molecules at several steps: one that diffuses away and one that remains bound to the target surface. How does the complement reaction remain localized when active products leave the surface?

Eric Goldman

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Problem 6

Based on its sequence similarity to Apobecl, which deaminates Cs to Us in RNA, activation-induced deaminase (AID) was originally proposed to work on RNA. But definitive experiments in $E$. coli demonstrated that AID deaminates Cs to Us in DNA. The authors of the paper expressed AID in bacteria and followed mutations in a selectable gene. They found that AID expression increased mutations about fivefold above the background level in the absence of AID expression. More importantly, they found that $80 \%$ of the induced mutations were $\mathrm{G} \rightarrow \mathrm{A}$ or $\mathrm{C} \rightarrow \mathrm{T}$. Does this fit with your expectation if AID-induced mutations arose by deamination of $\mathrm{C}$ to $\mathrm{U}$ in the DNA?
[Hint: imagine what would happen if the G:U mismatch created by AID was replicated several times; how would the sequences of the final mutations relate to the original G-C base pair?

Eric Goldman

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Problem 7

For many years it was a complete mystery how cytotoxic T cells could see a viral protein that seemed to be present only in the nucleus of the virus-infected cell. The answer was revealed in a classic paper that took advantage of a clone of T cells whose T cell receptor was directed against an antigen assoicated with the nuclear protein of the 1968 strain of influenza virus. The authors of the paper found that when they incubated high concentrations of certain peptides derived from the viral nuclear protein, the cells became sensitive to lysis by subsequent incubation with the cytotoxic T cells. Using various peptides from the 1968 strain and the 1934 strain (with which the cytotoxic T cells did not react $),$ the authors defined the particular peptide responsible for the T cell response (Figure $Q 24-1$ ).
A. Which part of the viral protein gives rise to the peptide that is recognized by the clone of cytotoxic T cells?
Why do not all viral peptides sensitize the target cells for Iysis by the cytotoxic T cells?
B. It is thought the MHC molecules come to the cell surface with peptides already bound. If that is so, how do you imagine that these experiments worked?
$24-8 \quad$ Working out the rules by which $\mathrm{T}$ cells interact with their target cells was complicated. Some of the key observations came from studying the way cytotoxic Tells killed cells infected with choriomeningitis virus (LCMV). Cytotoxic T cells derived from mice expressing "k-type" class I MHC proteins lysed LCMV-infected cells expressing the same k-type MHC protein, but they did not lyse infected cells from mice expressing "d-type" class I MHC proteins (Figure $Q 24-2$ ). Similarly, cytotoxic T cells from d-type mice lysed infected d-type cells, but not infected k-type cells. I CMV can kill both k-type and d-type mice.

Eric Goldman

Numerade Educator

Problem 8

Working out the rules by which $\mathrm{T}$ cells interact with their target cells was complicated. Some of the key observations came from studying the way cytotoxic T cells killed cells infected with choriomeningitis virus (LCMV). Cytotoxic T cells derived from mice expressing "k-type" class I MHC proteins lysed LCMV-infected cells expressing the same k-type MHC protein, but they did not lyse infected cells from mice expressing "d-type" class I MHC proteins (Figure $Q 24-2$ ). Similarly, cytotoxic T cells from d-type mice lysed infected d-type cells, but not infected k-type cells. LCMV can kill both k-type and d-type mice.
A. If homozygous d-type mice were bred to homozygous k-type mice to generate d-type/k-type heterozygous progeny, would you expect that cytotoxic T cells from these heterozygotes, when infected with ICMV, to be able to lyse infected d-type cells? How about infected k-type cells? Explain your answers.
B. Oddly enough, ICMV infection does not kill mice that lack a thymus-such as "nude" mice, so called because they also lack hair. If a thymus is transplanted back into a nude mouse, it will die when infected with LCMV. Suppose that a d-type/k-type heterozygous nude mouse was given a thymus from an d-type donor. Would you expect its cytotoxic T cells to be able to lyse infected d-type cells? How about infected k-type cells? Explain your answers.

Eric Goldman

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Problem 9

Before exposure to a foreign antigen, T cells with receptors specific for the antigen are a tiny fraction of the $\mathrm{T}$ cells-on the order of 1 in $10^{5}$ or 1 in $10^{6}$ T cells. After exposure to the antigen, only a small number of dendritic cells typically display the antigen on their surface. How long does it take for such antigen-presenting dendritic cells to interact with the antigen-specific T cells, which is the key first step in $\mathrm{T}$ cell activation and clonal expansion? The dynamics of the search process were examined by labeling dendritic cells red and T cells green, so that contacts in an intact lymph node could be scored visually using two-photon fluorescence microscopy (Figure $Q 24-3$ A). The frequency of contacts between dendritic cells and T cells from such experiments is given in Figure $24-3 B$. Assuming that 100 dendritic cells present the specific antigen, how long would it take them to scan $10^{5}$ T cells? How long for $10^{6} \mathrm{T}$ cells?

Eric Goldman

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Problem 10

At first glance, it would seem a dangerous strategy for the thymus to actively promote the survival, maturation, and emigration of developing T cells that bind weakly to self peptides bound to self MHC molecules. Would it not be safer to get rid of these T cells, along with those that bind strongly to such self-peptide-MHC complexes, as this would seem a more secure way to avoid autoimmune reactions?

Eric Goldman

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Problem 11

CD4 proteins on helper and regulatory T cells serve as co-receptors that bind to invariant parts of class II MHC proteins. CD4 is thought to increase the adhesion between T cells and antigen-presenting cells (APCs) that are initially connected only weakly by the T cell receptor bound to its specific peptide-MHC complex. To test this possibility, you label cell-surface MHC molecules with a fluorescently labeled peptide so that you can detect individual peptide-MHC complexes at the interface between the APCs and the T cells in a culture dish. To detect T cell responses-the sign of a productive contact-you load them with a $\mathrm{Ca}^{2+}$ indicator dye, as cytosolic $\mathrm{Ca}^{2+}$ increases when lymphocytes are active. You now count the peptideMHC complexes at a large number of interfaces (immunological synapses and measure the resulting uptake of $\mathrm{Ca}^{2+}$ in the adherent T cells (Figure $Q 24-4$, red circles). When you repeat the experiment in the presence of blocking antibodies against $\mathrm{CD} 4,$ you get a different result (blue circles). Do these results support or refute the notion that CD4 augments T cell receptor binding? Explain your answer.

Eric Goldman

Numerade Educator