Cell-mediated inhibition of proliferation and activation of alloreactive cytotoxic lymphocytes: maintenance of response potential of precursors and dissociation between proliferation and effector function of activated cytotoxic lymphocytes.
Adherent layers of macrophages (M phi-c) generated in vitro from splenic precursors inhibit lymphoproliferative responses to mitogen and to alloantigen without inhibiting the production of interleukin-2 (IL-2). Analysis of spleen cells stimulated for 48 hr in the presence of M phi-c indicated that both blastogenesis (increased cell mass) and expression of IL-2 receptors (7D4 determinants) were reduced. Analysis of BrdU incorporation (frequency of S-phase cells) and total cellular DNA revealed that the M phi-c inhibited the progression from G1 to S phase of cell cycle. The M phi-c not only inhibited the proliferative response to alloantigen but also prevented the generation of alloreactive cytotoxic T cells. The M phi-c were shown not to inhibit CTL responses by eliminating the stimulators or by inactivating precursors or inducing suppressors. The M phi-c were affecting the induction of CTL activity since the M phi-c did not affect the expression of cytolytic activity by activated CTL. The M phi-c did inhibit the proliferation of the activated CTL, suggesting that although cytolytic activity can be expressed in G1 phase of cell cycle, the activation of cytolytic activity in CTL-P may require a G1 to S phase transition. The cells recovered from 5-day MLC incubated in the presence of M phi-c were fully capable of generating a subsequent CTL response. This is in contrast to cells recovered from unstimulated cultures (no M phi-c) which have lost the ability to generate CTL responses. The M phi-c therefore prevent the generation of CTL responses in a totally reversible fashion, so as to allow activation and proliferation of CTL-P which have been removed from the influence of the M phi-c. These observations are discussed in the context of the currently hypothesized role of tissue macrophages in microenvironmental regulation.
D000818:Animals; D003602:Cytotoxicity, Immunologic; D005260:Female; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D007376:Interleukin-2 / Q000378:metabolism; D007399:Interphase; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D011971:Receptors, Immunologic / Q000378:metabolism; D015375:Receptors, Interleukin-2; D013154:Spleen; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
D007376:Interleukin-2; D011971:Receptors, Immunologic; D015375:Receptors, Interleukin-2