Definition and Core Concepts

Cell-mediated immunity is a specific type of acquired immune response mediated by sensitised T-cells, rather than by antibodies.
This form of immunity is transferred from a donor to a recipient using intact lymphocytes, not with antisera.
It is primarily stimulated by T-helper type I (Th1) lymphocytes and the cytokines released in response to antigens.
CMI targets microbes that survive phagocytosis and those that infect non-phagocytic cells.

Clinical Functions of Cell-Mediated Immunity

Function Category	Specific Details and Applications
Intracellular Pathogens	Confers immunity against obligate intracellular bacteria (Mycobacterium tuberculosis, Mycobacterium leprae, Brucella). Protects against viruses (smallpox, measles, mumps) and fungi (Histoplasma capsulatum, Blastomyces dermatitidis). Targets intracellular parasites (Toxoplasma gondii, Leishmania donovani).
Immunological Surveillance	Actively removes virus-infected cells and provides immunity against cancer.
Pathology and Autoimmunity	Plays a central role in the pathogenesis of delayed hypersensitivity (type IV) reactions. Drives tissue damage in certain autoimmune diseases, such as autoimmune thyroiditis and encephalitis.
Transplantation	Participates centrally in transplant rejection and graft-versus-host reactions.

Only T-cell-dependent antigens have the capacity to induce CMI.
Killed vaccines or non-living antigens do not naturally induce CMI unless administered with Freund's adjuvants.
The induction of CMI involves three sequential stages:

Antigen-presenting cells (APCs), such as macrophages, internalise exogenous proteins via endocytic vesicles.
These proteins are exposed to cellular proteases, generating peptides of 10 to 30 amino acids within intracellular vesicles.
The endosomal vesicles subsequently fuse with exocytic vesicles containing Class II Major Histocompatibility Complex (MHC) molecules for surface presentation.

T-cells can only recognise antigens when they are presented alongside MHC molecules.
CD8+ T-cells specifically recognise foreign antigens combined with Class I MHC molecules.
- Following recognition, CD8+ cells differentiate into cytotoxic (Tc) and suppressor (Ts) lymphocytes.
CD4+ T-cells recognise combinations of antigen and Class II MHC molecules.
- They subsequently differentiate into helper (Th) and delayed hypersensitivity (Td) cells.
Sensitised T-lymphocytes undergo blast transformation, clonal proliferation, and differentiation into memory and effector cells.

Activated lymphocytes release lymphokines, which are biologically active products.
These lymphokines are responsible for the various physical manifestations of CMI and mediate the ultimate lysis of the target cells.

Skin tests are highly useful to detect delayed hypersensitivity reactions to common antigens.
Antigens utilised include purified protein derivative (PPD) in the tuberculin test, dinitrochlorobenzene, or dinitrofluorobenzene.
The absence of reactions to these established skin tests suggests an impairment of CMI.

Test Name	Underlying Principle and Clinical Application
Migration Inhibiting Factor (MIF) Test	Cultured T-cells produce MIF upon exposure to sensitising antigens. This factor prevents human peripheral leukocytes from migrating out of capillary tubes, allowing semi-quantitative assessment.
Lymphocyte Blast Transformation	Sensitised T-lymphocytes undergo blast transformation when exposed to specific antigens or mitogens like phytohemagglutinin. DNA synthesis increases and is measured by the incorporation of tritiated thymidine.
Enumeration by Flow Cytometry	A fluorescence-activated cell sorter counts T-cells and subsets using specific monoclonal antibodies. The normal CD4 to CD8 ratio is $\ge$ 1.5, but falls below 1 in Acquired Immunodeficiency Syndrome (AIDS).
Rosette Formation	Most T-cells attach to sheep erythrocytes to form structures called E-rosettes. Counting these E-rosettes provides an estimation of circulating T-cells.
Molecular Methods	Flow cytometry can assess alteration of surface markers like CD25 and CD71 post-activation. ELISPOT assays measure specific T-cell cytokine production. Interferon-gamma release assays (IGRA) measure cytokine production in response to specific M. tuberculosis antigens.

CMI can be systemically transferred to a host using an extract from immunised leukocytes called transfer factor.
Transfer factor is a low molecular weight nucleotide (2000 to 4000 Da) that is uniquely non-antigenic.
It is believed to stimulate the release of lymphokines from already sensitised T-lymphocytes.
Clinical applications include treating disseminated infections associated with deficient CMI, such as tuberculosis and lepromatous leprosy.
It is also utilised in managing malignant melanoma and T-cell-deficient syndromes like Wiskott-Aldrich syndrome.