The fourth dimension in immunological space: how the struggle for nutrients selects high-affinity lymphocytes.
Lymphocyte activation via the antigen receptor is associated with radical shifts in metabolism and changes in requirements for nutrients and cytokines. Concomitantly, drastic changes occur in the expression of pro-and anti-apoptotic proteins that alter the sensitivity of lymphocytes to limiting concentrations of key survival factors. Antigen affinity is a primary determinant for the capacity of activated lymphocytes to access these vital resources. The shift in metabolic needs and the variable access to key survival factors is used by the immune system to eliminate activated low-affinity cells and to generate an optimal high-affinity response. In this review, we focus on the control of apoptosis regulators in activated lymphocytes by nutrients, cytokines, and costimulation. We propose that the struggle among individual clones that leads to the formation of high-affinity effector cell populations is in effect an 'invisible' fourth signal required for effective immune responses.
Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands.
Felix M
FM
Wensveen
Klaas P J M
KP
van Gisbergen
Eric
E
Eldering
D000818:Animals; D017209:Apoptosis; D016207:Cytokines; D005502:Food; D006801:Humans; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011946:Receptors, Antigen / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction
D016207:Cytokines; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D011946:Receptors, Antigen