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).^[1]The role of Th17 and Th1 cells in CMI may vary depending on stimulants.^[2]

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).^[3]

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.^[2]

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.^{[1, 2]}In addtion, IL-4 KO mice revealed attenuated CH responses.^[4]Cytotoxic CD8⁺ T cells that produce IL-17A (Tc17 cells) are also implicated in induction of CH in rodent models.^[5]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.

Pathophysiology

A DTH reaction in the skin is initiated when certain Ags are presented by Ag-presenting cells (APCs) (ie, Langerhans cells to sensitized memory T cells). The Ag presentation and subsequent T-cell activation via CD3 and T-cell Ag receptor (TCR)(CD3/TCR) complex elicit an influx of macrophages, monocyte, and lymphocytes at the site of Ag exposure. These cells then produce inflammatory cytokines including tumor necrosis factor-α (TNF-α), IL-17A, and IFN-γ. At the onset of the DTH reaction, vasopermeability is increased by serotonin and histamine, and adhesion molecules are up-regulated in the vascular endothelium, so that additional cellular components migrate into the local site of Ag presentation.

The APCs present Ags complex in the groove of major histocompatibility complex (MHC) molecules expressed on the cell surface of the APCs. For most proten antigens or haptens associated with DTH skin reaction, CD4⁺ T cells are presented with Ags bound to MHC class II alleles, human leukocyte antigen (HLA)-DR, -DP, and –DQ. Specific MHC class II alleles are associated with excessive immune activation to certain Ags. For example, abacavir, an antiviral drug, causes severe adverse drug reactions exclusively in subjects with HLA variant B*57:01.^{[6, 7]}Abacavir reactions are driven by drug-specific activation of cytotoxic CD8⁺ cells and this is implicated with abacavir's binding to the F pocket of the peptide-binding groove of HLA-B*57:01, resulting in alloreactive T-cell responses.^[8]

T cells recognize Ags through TCRs, which are composed of heterodimers containing constant and variable regions (TCR α/ß and TCR γ/δ) analogous to the constant and variable regions of immunoglobulin. Most delayed-type hypersensitivity responses are elicited through TCR α/β T cells. TCR γ/δ is commonly expressed on T cells in the epithelium boundaries with limited TCR diversities. The function of TCR γ/δ T cells are not well understood in humans.

Ag elicited TCR activation is mediated by CD3 composed of γ, δ, and ε proteins and intracellular ζ chains. This CD3/TCR complex activation requires additional signaling mediated by CD4 or CD8 molecules which are physically associated with the CD3/TCR complex. In addition, Ag-mediated TCR activation requires Ag-independent signaling via co-stimulatory molecules which are not physically associated with the CD3/TCR complex. Co-stimulatory molecules that mediate activation signals such as CD28 and ICOS are constitutively expressed on T cells while inhibitory co-stimulatory molecules such as CTLA-4 (CD152) and PD-1 are up-regulated following T cell activation to abrogate excessive inflammatory responses.

DTH responses to some organisms are predominantly mediated by CD8⁺ cytotoxic T cells and effector stage Th1 cells augment CD8⁺ T cell activation. CD8⁺ T cells activate macrophages via CD40-CD40L interactions and production of Th1 cytokines including IFN-γ. The differences in T cell immune responses to intracellular microbes determine disease outcomes in certain diseases. For example, ineffective CMI is observed in patients with lepromatous leprosy with high Mycobacteria leprae load in macrophages and destructive skin lesions. While, in tuberculoid leprosy, strong CMI induces granulomas with less M Leprae load but severe sensory nerve defects.

IFN-γ is the key cytokine that plays the dominant role in DTH and is a major activator of macrophage-monocyte lineage cells; it augments phagocytic function and production of reactive oxygen intermediates (ROIs). IFN-γ also up-regulate T cell activation markers (CD69, CD71, CD25, and HLA-DR) and MHC molecules on APCs, promotes differentiation of Th1 cells while suppressing Th2 cell differentiation, and promote isotype switching of antibody (Ab) to facilitate Ab-mediated phagocytic cell immune responses. Recent studies also revealed a role of Th17 cells that produce IL-17A, IL-17F, IL-21, and IL-22.^{[1, 2, 9, 10]}IL-17A was reported to amplify human contact hypersensitivity (CH) by rendering keratinocytes to susceptible to ICAM-1 dependent, Ag-non-specific T cell killing.^[11]

IFN-γ also exerts regulatory actions on CD4⁺ Th cells.^[12]IFN-γ affects activation-induced cell death of Th cells, contributing to lymphocyte homeostasis. IFN-γ is also reported to covert CD4⁺ CD25^- Th cells into inducible CD4⁺ CD25⁺ regulatory T (Treg) cells by inducing Foxp3 expression. Lack of such IFN-γ actions is likely associated with excessive DTH reactions in patients with defects of IL-12–IFN-γ signaling pathways, which results in lack of IFN-γ actions.

TNF-α is also essential for DTH responses. Major cellular sources of TNF-α include macrophages and Th1 cells but this cytokine is also produced by many other lineage cells. TNF-α induces chemokine production from macrophages and endothelial cells and it also up-regulates expression of adhesion molecules on vascular endothelial cells, resulting in massive influx of inflammatory cells. In DTH responses to poison ivy and nickel, mast cells are likely a major source of TNF-α, in addition to production of other inflammatory mediators including histamine. TNF-α also induces inflammatory cytokines including IL-1. In rodent models of DTH, IL-1 but not IL-33 was found to be crucial for IFN-γ induced DTH reactions.^[13]

Another key cytokine associated with DTH responses is IL-12. IL-12 is mainly produced by APC and Th1 cells. IL-12 augments production of IFN-γ and promotes Th1 cell differentiation. It also enhances cytolytic actions of NK and CD8⁺ T cells. IL-18 was also shown to augment IFN-γ production in the presence of IL-12. Osteopontin (OPN), a phosphoglycoprotein produced in the tissue, has also a role for promoting Th1 and Th17 driven DTH by supporting APC migration and IL-12 expression.^{[14, 15]}

A defect in DTH reaction is best illustrated in the gene mutations of IFN-γ and IL-12 pathways. Gene mutation of IFN-γ receptor 1 (IFNGR1) is characterized by ineffective granuloma formation and disseminated infection of atypical Mycobacterium species, BCG, and Salmonella species.

The IFNGR1 gene consists of 7 exons (50 kb) and is highly polymorphic. Mutations identified thus far include frameshift deletions, insertion, a splice mutation, and missense mutations at the up-stream end of the gene. These mutations generally lead to absence of IFN-γ receptor protein expression or nonfunctional binding sites of IFN-γR for IFN-γ. This leads to impaired macrophage activation and resultant decreased production of TNF-α and ROIs. The gene mutations of IFNGR2 also cause similar clinical pictures. In contrast, mutations in IFNGR1 at a downstream hotspot disrupt the intracytoplasmic domain and result in a dominantly expressed disorder with milder clinical features.^[16]

TH17 and Tc17 cells are also implicated with DTH and CH responses. For example, nickel-specific Th clones established from patients with nickel CH was shown to produce IL-17A.

Down-regulation of CMI in the immunocompetent host is an active process and important for minimizing tissue injury caused by DTH. Counter-regulatory cytokines such as IL-10 down-regulate production of Th1/Th17 cytokines or counteracts to Th1/Th17 cytokines. Naturally occurring and inducible regulatory T (Treg) cells also play a crucial role in this process, partly via production of IL-10 and TGF-ß.

Drugs that block components of DTH responses include antihistamines, histamine 2 (H2) receptor antagonists, and prostaglandin antagonists such as indomethacin. As indicated before, IFN-γ can augment induction of inducible Treg cells that produce IL-10 and TGF-ß in the late stage of DTH–induced inflammation to self-limit DTH reactions.^[12]. It should be noted that effector Th cells can change lineage-specific functions depending on the microenvironment. That is, Th17 cells can acquire the ability of secreting Th1 cytokines and Th17 cells can also switch to Treg phenotype.^{[9, 10]}Such flexibility is thought to be helpful for maintaining immune homeostasis and minimizing tissue damage associated with DTH responses in addition to effective microbial clearance.

Frequency

United States

More than 80% of healthy children aged 12-36 months mount positive DTH skin test reactivity to a Candida antigen. In the absence of a skin DTH response, evaluating CMI with in vitro lymphocyte proliferative responses to the specific Ag is necessary to confirm the anergic state.

Anergy is observed in patients with malnutrition, severe atopic dermatitis, and severe infections caused by M tuberculosis, measles, mumps, HIV, influenza, mononucleosis, lepromatous leprosy, and certain fungi. Anergy is also observed in patients who have recently received the measles, mumps, and rubella (MMR) vaccine, patients with sarcoidosis, or patients with parasitic infestations. In addition, immunosuppressive drugs, such as cytotoxic medications and corticosteroids, lead to anergy. Malignancy, especially malignant lymphomas, also induces anergy.

It should be noted that DTH reactions in patients with impaired IFN-γ and IL-12/IL-23 pathways tend to reveal excessive DTH reactions. In contrast, in patients with autosomal dominant or autosomal recessive hyper immunoglobulin E (IgE) syndrome with STAT3 mutations or DOCK 8 deficiency, decreased DTH responses against Candida may be observed due to deficiency of Th17 cells.^{[17, 18]}

International

DTH reactivity to tuberculin is elicited by BCG vaccination. BCG is the most commonly administered vaccine throughout the world; however, it is not used in the United States.

Mortality/Morbidity

DTH skin testing is almost never associated with mortality or morbidity. The major error is associated with failure of differentiating anergy from negative DTH reactivity. Anergy may result from overwhelming infection such as sepsis or immunodeficiency. Secondary immunodeficiency is commonly due to therapy with corticosteroids, chemotherapy, calcineurin inhibitors (eg, cyclosporine, tacrolimus), and various monoclonal antibodies directed against the immune system.

Patients with T-cell immunodeficiency diseases such as severe combined immunodeficiency (SCID) are anergic.

Patients with mutations in IL12P40 or in IL12RB1 may show a positive, often excessive, DTH reactivity through activation of other components of DTH responses such as IL-17 and perhaps due to lack of regulatory effects of IFN-γ.

Mutations in IFNGR2, STAT-1, IL12P40, and IL12RB1 are autosomal recessive. Mutations found in complete IFN-γR deficiency are also autosomal recessive. Mutations in IFNGR1 that affect the downstream intracytoplasmic domain are autosomal dominant and are manifested as partial IFN-γR deficiency with less severe clinical manifestations. Patients with complete IFN-γR deficiency often succumb to death from overwhelming infection caused by nontuberculosis mycobacteria (NTM) and BCG at young age. Severe cytomegalovirus (CMV) infection is also described in these patients.

Mutations partially impairing IFN-γ signaling pathway may be manifested with milder mycobacterial infection, nontyphus Salmonella infection, Legionella infection, and listeriosis.

Race

Some individuals from the Mediterranean area have mutations leading to insufficient IFN-γ function. Specifically, a family from Tunisia, several families from Malta, and 1 family from Italy have been reported. Genetic defects involving the IFN-γ/IL-12 axis are now increasingly reported in other races.

Sex

Anergy to BCG and of idiopathic disseminated BCG infection are equally distributed among males and females. As expected in autosomal recessive gene mutations, IFNGR1, IL12P40, and IL12RB1 mutations are found with equal frequency in males and females.

Age

DTH reactivity to Candida Ag can be detected in infants as young as 3-4 months, but reactivity depends on exposure to the candida Ag. Positive DTH reactivity to tetanus toxoid requires completion of the primary immunization series of 3 injections administered 4-6 weeks apart; only one third of infants have a positive response to tetanus after the first dose of DTaP immunization. Patients with IFNGR1/IFNGR2 mutations that cause complete loss of IFN-receptor expression or IFN-γ–mediated signaling have presented as infants or in early childhood with disseminated BCG or NTM infections. This age-related infection seems to reflect the age of exposure to the causative organisms.

Clinical Presentation

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