During recovery from cytomegalovirus infection T-lymphocyte subsets become selectively responsive to activation and have depressed interleukin 2 (IL2) secretion and IL2 receptor expression.
The ability to induce lymphocyte activation with Concanavalin A (Con A) was suppressed in spleen cell cultures derived from BALB/c mice acutely infected with murine cytomegalovirus (MCMV) when compared to cultures derived from control, uninfected mice. This immunosuppression was observed as a reduced incorporation of 3H-thymidine in the lymphocyte proliferative response to Con A, was highly correlated with reduced secretion of interleukin 2 (IL2), and could not be augmented by addition of exogenous IL2. The degree of suppression of both the proliferative response and IL2 secretion was directly dependent on the infecting virus dose and on the time post-infection. At weekly intervals during infection, fluorescein-labeled monoclonal antibodies to various T-lymphocyte surface markers were used to stain spleen cells from control or MCMV-infected mice before or after Con A activation. Analysis of stained spleen cells by flow cytometry revealed several unusual responses to activation signals in lymphocytes derived from mice with acute MCMV-induced immunosuppression. At 4 days post-infection T-lymphocytes of each subset [Thy 1.2 (pan T), L3T4 (T-helper/inducer), Lyt 2 (T-cytotoxic/suppressor) and Lyt 1 (subset of Thy 1.2)] were each present in the spleen but each was in reduced percentage of the total spleen T cell population compared to control (52% to 75% of controls). At this time post-infection these cells were non-responsive to Con A activation as shown by inability to induce 3H-thymidine uptake, IL2 secretion or IL2 responsiveness and an inability to demonstrate an IL2 receptor-positive (IL2R+) population. By 11 days post-infection all tested subsets of T-lymphocytes (Thy 1.2+, L3T4+, Lyt 2+ and Lyt 1+) were in normal control range in fresh spleen. However, only Thy 1.2+L3T4+ (T-helper/inducer) cells were responsive to Con A activation. 3H-thymidine uptake and IL2 secretion were at levels of about 60% of the control but, surprisingly, cells were unresponsive to addition of exogenous IL2 and few, if any, of these cells were found to express IL2 receptors. By 18 days post-infection, when 3H-thymidine uptake could be induced at control level, Thy 1.2+, L3T4+, and Lyt 2+ (T-cytotoxic/suppressor) cells were each responsive to Con A activation at levels comparable to control but Lyt 1+ and IL2 R+ cells were still substantially suppressed (ca. 35% to 40% of control value). Detection of Lyt 1+ subset and IL2 R+ cells after Con A activation did not near control levels until very late in the recovery process (day 25).(ABSTRACT TRUNCATED AT 400 WORDS)
Nicholas
J A
JA
Cancer and Viral Diseases Research, Upjohn Company, Kalamazoo, MI 49001.
Levely
M E
ME
Brideau
R J
RJ
Berger
A E
AE
D000818:Animals; D002478:Cells, Cultured; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000503:physiopathology; D005260:Female; D005434:Flow Cytometry; D007108:Immune Tolerance; D007376:Interleukin-2 / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis*; D012016:Reference Values; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000145:classification* / Q000276:immunology
D007376:Interleukin-2; D015375:Receptors, Interleukin-2