Natural T Cell Immunity to Intracellular Pathogens and Nonpeptidic Immunoregulatory Drugs

F.      Poccia; C.      Agrati; G.      Ippolito; V.      Colizzi; M.      Malkovsky

Abstract

Natural T (NT) lymphocytes recognize infected cells or microbial compounds without the classical genetic restriction of polymorphic major histocompatibility complex (MHC) molecules. This innate recognition pathway results in a broad and rapid antimicrobial response that may be critical for controlling the spread of intracellular pathogens, requiring the elimination of the infecting agent from both extracellular spaces and host cells. NT cells are mainly composed of alpha beeta and gama delta T lymphocytes that express natural killer (NK) receptors and recognize preferentially various nonpeptidic antigens. Similar to NK cells, NT lymphocytes can see and kill target cells deficient in the expression of one or more MHC class I molecules. NT cells expressing the alpha beeta TCR can recognize lipid and lipoglycan antigens presented in the context of nonpolymorphic CD1 molecules, whereas phosphocarbohydrates and akilamines induce constitutive responses in most V gama 9V delta 2 NT lymphocytes. The remaining fraction of gama delta NT cells express the Vdelta 1 chain associated with different V gama-chains and may directly recognize self-antigens such as MICA, MICB or CD1 molecules. It is possible that NT lymphocytes may play two opposite roles during intracellular infections. First, in the acute phase, they may be critical for the initiation of pathogen elimination. Second, in the chronic phase, NT cells may be dangerous, if their potential autoreactivity is not well controlled. It is conceivable that novel strategies of immune intervention against emerging and re-emerging intracellular pathogens, such as human immundeficiency virus (HIV), hepatitis-C virus (HCV) and Mycobacterium tuberculosis (MTB) may involve the control of NT cell activation(slash )anergy by (nonpeptidic) immunoregulatory drugs.

Keywords: Natural T Cell Immunity, Intracellular Pathogens, Nonpeptidic, Immunoregulatory Drugs, histocompatibility complex (MHC), Natural killer, Mycobacterium tuberculosis (MTB), immundeficiency virus (HIV, CD1 molecules, Hepatitis-C Virus HCV, MICA