A role for transforming growth factor-beta 1 in regulating natural killer cell and T lymphocyte proliferative responses during acute infection with lymphocytic choriomeningitis virus.

The role of transforming growth factor beta 1 (TGF-beta 1) in regulating NK and T cell proliferation during acute viral infections was investigated. After infection of mice with lymphocytic choriomeningitis virus, NK cell proliferation peaks on day 3 and subsides by days 5 to 7 postinfection, whereas T cell proliferation peaks on day 7 and declines by days 9 to 14 postinfection. As TGF-beta 1 has been shown to inhibit lymphocyte proliferation in culture, the production and function of TGF-beta 1 during infection was evaluated in this model. Northern blot analysis demonstrated that the accumulation of TGF-beta 1 transcripts remained relatively constant in total splenic leukocytes during infection. The Mv 1 Lu mink lung cell bioassay was modified and used to evaluate the production of biologically active TGF-beta 1 during infection. Media conditioned with splenic leukocytes isolated from infected mice contained factors that inhibited DNA synthesis by the Mv 1 Lu cells. Low levels of inhibition were observed with conditioned media prepared on day 3 postinfection and high levels of inhibition were observed with conditioned media prepared on days 5 through 14 postinfection. Neutralization with antibodies specific for TGF-beta 1 demonstrated that TGF-beta 1 contributed to the inhibitory activity. As TGF-beta 1 was produced at times coinciding with the decline in NK cell proliferation, the TGF-beta 1 sensitivity of in vivo-elicited NK cells was evaluated. In vitro and in vivo studies demonstrated that NK cell proliferation was extremely sensitive to inhibition by TGF-beta 1. In culture, TGF-beta 1 had an ID50 of 8 pg/ml for inhibiting DNA synthesis by blast NK cells. In vivo, administration of a total of 0.18 micrograms of TGF-beta 1 resulted in a 93% inhibition of NK cell-mediated lytic units per spleen on day 3 postinfection. The inhibition was a result of a block in NK cell proliferation, as administration of TGF-beta 1 profoundly suppressed the appearance of blast size NK cells and the incorporation of [3H] thymidine by NK cell-enriched, blast lymphocyte populations on day 3 postinfection. In contrast to NK cell proliferation, T cell proliferation was not inhibited by up to 100-fold higher concentrations of the factor in vitro or in vivo. Taken together, these data demonstrate that TGF-beta 1 is an important regulator of NK cell proliferation in vivo. Furthermore, the results indicate that differential sensitivity to TGF-beta 1 may contribute to the coordination of NK and T cell responses during viral infections.