A 24-year-old nurse comes to the office for his annual wellness visit that includes tuberculosis screening. The patient has no chronic medical conditions and does not have recent fever, cough, or other health changes. He receives an intradermal injection of tuberculin on the inner surface of his forearm. Two days later, he has a distinct area of induration 20 mm across at the injection site. Which of the following interactions likely contributes the most to the development of this patient's skin reaction?
Tuberculin skin testing (TST) introduces purified proteins from Mycobacterium tuberculosis into the dermis. Because M tuberculosis is primarily countered by the cell-mediated immune response (CMIR), previously infected patients have primed, antigen-specific CD4 T lymphocytes that rapidly replicate and mature in response to tuberculin antigen re-exposure.
T-lymphocyte activation is a 2-step process:
Activated CD4 T lymphocytes release inflammatory cytokines (eg, IL-1, IL-6, TNF alpha) that stimulate/recruit other immune cells and increase vascular permeability, forming an indurated wheal of inflammation following TST exposure. Tuberculin reactions appear 24-72 hours after antigen exposure due to delays between initial antigen processing by APCs, T-cell activation, and amplification of the cellular response.
(Choice A) CD14 is a pathogen-associated molecular pattern receptor on macrophages that recognizes lipopolysaccharides and rapidly activates the innate immune response; it does not participate in TST.
(Choice B) CD16 is a receptor on natural killer cells that binds to the FC portion of IgG attached to foreign antigens on infected cells. Binding triggers lysis of the infected cell via antibody-dependent cellular cytotoxicity (part of the CMIR). Antibodies do not play a significant role in TST.
(Choice C) CD18 on circulating neutrophils binds to ICAM-1 on the endothelium, allowing neutrophils to extravasate into tissue. Neutrophils are not a major part of TST reactions.
(Choice E) CTLA4 is an immune checkpoint expressed by regulatory and activated T cells. It mutes the CMIR by competing with the T-cell costimulatory ligand CD28 for binding CD80/86 (ie, B7) on dendritic cells (APCs). Because CTLA4 binds with greater affinity than CD28 to CD80/86, it slows the activation of T cells in areas with active inflammation.
Educational objective:
Tuberculin skin testing triggers a type IV delayed-hypersensitivity reaction in patients with previous infection due to the presence of primed, antigen-specific CD4 T lymphocytes. These lymphocytes recognize tuberculin proteins displayed on antigen-presenting cells (APCs) and become activated following a costimulatory interaction between CD28 on the T cell and CD80/86 on the APC.