Background
Cell-mediated immunity (CMI) is a T-cell–mediated defense mechanism against microbes that survive within phagocytes or infect nonphagocytic cells. CMI functions to enhance antimicrobial actions of phagocytes to eliminate microbes. CMI manifests as delayed type cellular immune responses as typically seen in Mantaux test. This T-cell–mediated activation of phagocytes depends on interferon gamma (IFN-γ), a major cytokine produced by type 1 T-helper (Th1) cells. However, anti-IFN-γ neutralizing antibodies (Abs) do not completely abrogate CMI. IFN-γ or IFN-γR knock out (KO) mice do reveal attenuated CMI. These results indicate that CMI cannot be solely attributed to IFN-γ – mediated Th1 responses.
The identification of Th17 cells, which produce interleukins (ILs) – 17A, IL-17F, IL-21, IL-22, granulocyte-macrophage colony-stimulating factor (GM-CSF), and many other factors shed a light on the previously observed CMI in the absence of IFN-)γ. IL-17 KO mice did display attenuated delayed-type hypersensitivity (DTH) against bovine serum albumin and bacille Calmette-Guérin (BCG).
The role of Th17 and Th1 cells in CMI may vary depending on stimulants.
Phagocytic cell activation and inflammation induced by CMI can cause tissue injury, typically called delayed-type hypersensitivity. In experimental animal models, delayed-type hypersensitivity responses are characterized by a granulomatous response consisting of macrophages, monocytes, and T lymphocytes. In skin, keratinocytes are also thought to have a role.
DTH responses in the skin have been used to assess CMI in vivo. An antigen (Ag) is introduced intradermally (ID), and induration and erythema at 48-72 hours postinjection indicate a positive reaction. Positive responses require the subject’s exposure to the Ag at least 4-6 weeks prior to skin testing. The lack of a DTH response to a recall Ag is often regarded as an evidence of anergy. In the absence of underlying diseases, anergy may indicate primary or secondary T-cell immunodeficiency. The prototype recall Ag is Mycobacterium tuberculosis; other commonly used Ags for DTH responses in humans include tetanus, Candida and Trichophyton species, and mumps. Several fungi and streptococci Ags are no longer available or not recommended for clinical use.
DTH responses in the skin can also occur as contact hypersensitivity (CH) to certain chemicals, including nickel, dinitrochlorobenzene (DNCB), and picryl chloride. DTH reaction can also occur with various medications, including sulfonamides, phenytoin, and carbamazepine. These small chemicals are believed to act as haptens or activate T cells by directly binding to T cell Ag receptor (TCRs)/major histocompatibility complex (MHC).
Originally, CH was thought to be skin DTH reaction. However, recent studies indicate that CH can be caused by different immune mechanisms. That is, in CH, CD4+ T cells are major effector cells, with CD8+ cell playing a regulatory role at least in certain model systems. In rodents, chemically induced CH was reported by attenuated by recombinant IFN-γ.
CH induced by chemicals is enhanced by IL-17A, which induces production of IL-6, IL-8, GM-CSF, and upregulated expression of intercellular adhesion molecule (ICAM)-1 in human keratinocytes.
In addtion, IL-4 KO mice revealed attenuated CH responses.
Cytotoxic CD8+ T cells that produce IL-17A (Tc17 cells) are also implicated in induction of CH in rodent models.
Thus, at least in rodent models, Th17 and Th2 cytokines have a role in induction of CH; Th17 cells produce IL-17A, and Th2 cells are a major source of IL-4.