Editors' ChoiceImmunological Tolerance

T Cells Complementing Tolerance

Science's STKE  28 Jan 2003:
Vol. 2003, Issue 167, pp. tw47-TW47
DOI: 10.1126/stke.2003.167.tw47

Kemper et al. investigated the factors governing lymphocyte differentiation into T-regulatory 1 (Tr1) cells and uncovered a role for CD46, a protein involved in complement regulation that also acts as a receptor for several human pathogens, in T cell-mediated immunological tolerance. To respond appropriately to innocuous and harmful stimuli, cells in the immune system must generate defensive responses to antigens associated with pathogens but not to self antigens. One mechanism whereby lymphocytes avoid potentially destructive autoimmune reactions involves the active suppression of T helper cells by Tr1 cells, a class of CD4+ lymphocytes that produce interleukin 10 (IL-10). Kemper et al. stimulated mixed populations of cultured CD4+ human peripheral blood lymphocytes with antibodies to cell surface proteins and discovered that the combination of CD3 and CD46 promoted IL-10 production. When CD4+ lymphocytes were sorted by cell-surface phenotype into naïve cells (CD45RA+CD45RO-), memory cells (CD45RA-CD45RO+), and CD45RA+CD45RO+ cells, antibodies to CD3 and CD46 given in combination with interleukin-2 (IL-2) elicited IL-10 production in naïve and CD45RA+CD45RO+ cells. Cells initially stimulated with antibodies to CD3 and CD46 acquired a memory-cell phenotype and subsequently produced IL-10 after stimulation with CD3 alone. Although CD3 and CD46 antibodies stimulated T cell proliferation, medium from these cells inhibited the proliferation of fresh CD4+ T cells, consistent with a Tr1 phenotype. This inhibition was blocked with neutralizing antibodies to IL-10. These data implicate CD46 in Tr1 cell development and suggest that the complement system may play a role in T cell-mediated tolerance.

C. Kemper, A. C. Chan, J. M. Green, K. A. Brett, K. M. Murphy, J. P. Atkinson, Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype. Nature 421, 388-392 (2003). [Online Journal]