6.5.2　Cytotoxic T Lymphocytes and Disease

Allergic contact dermatitis is a delayedtype hypersensitivity reaction mediated by hapten-specific T cells.During the sensitization phases, both CD4+and CD8+T-cell precursors are activated in the draining lymph nodes by presentation of haptenated peptides.Re-challenge with the hapten induces the recruitment of T cells at the site of challenge, that is, the skin; this induces inflammatory signals and apoptosis of epidermal cells, leading to the development of a skin inflammatory infiltrate and to clinical symptoms.The respective roles of CD4+and CD8+T cells in the development of the inflammatory reaction are still the subject of controversial discussions.Experimental evidence,however, suggests that in contact hypersensitivity responses to strong haptens, CD8+T cells are the key effector cells, whereas CD4+T cells are endowed with downregulatory functions.Ongoing studies will have to confirm that the pathophysiology of human allergic contact dermatitis is indeed comparable to the murine contact hypersensitivity [139-142].

Organ-specific autoimmune diseases are caused by an immune response directed to a target antigen unique to a single organ; thus, manifestations are largely limited to that organ.Such autoimmune diseases may involve direct cellular damage mediated by antibodies and/or CTLs.For example, in Hashimoto’s thyroiditis, both antibodies and T cells are involved.In insulin dependent diabetes mellitus and multiple sclerosis, the etiological function of CTLs is well established.Furthermore,recent reports suggest a function of CTLs in the pathogenesis of skin diseases such as systemic sclerosis and paraneoplastic pemphigus.However, the strongest and most direct evidence for a key role of CTLs in the pathogenesis of autoimmune disease exists for vitiligo.Vitiligo is a common hypopigmentary disorder that affects approximately 2% of the world population.The loss of skin pigmentation is caused by the selective destruction of melanocytes.The initiation and the ultimate pathway of melanocytic destruction in vitiligo are, however, not fully understood.Observations of vitiligo accompanying metastatic melanoma (melanoma-associated hypopigmentation) support a role of autoreactive CTLs recognizing shared melanocyte differentiation antigens [143-145].(https://www.daowen.com)

The largest body of evidence that CTLs are involved in the clinical course of disease exists for neoplastic disease.Most of the work focuses on the function of CTLs in the control (or lack of control) of tumors.In 1982, Van Pel and Boon demonstrated the generation of a protective immune response against an otherwise non-immunogenic murine tumor.This was the first experimental evidence that lack of immunogenicity of a tumor is due to the tumor’s inability to activate the immune system rather than to the absence of tumor antigens.Since then it has become clear that CD8+CTLs alone or sometimes in combination with CD4+Th cells constitute the effector arm of the adaptive immune response to cancer.Thus, it is not surprising that much effort is spent on identification and characterization of tumor antigens for use in active immune therapy.To this end,the number of known T-cell epitopes derived from tumor-associated antigens exceeds 200 and is still increasing.The proteins from which these peptide antigens are derived can be divided into different groups.It should be noted, however, that the distinctions between some of the groups are somewhat arbitrary [146,147].