CD4 T cells in murine acquired immunodeficiency syndrome: polyclonal progression to anergy.

Abstract

SummaryWe have examined the kinetics of changes that occur in the helper T cell subset during murine acquired immunodefidency syndrome, which occurs after infection with the mix of viruses known as BM5. We find that there is expansion of the CD4 T cells by 2 wk, 50% of the CD4 T cells become large as the disease progresses, and the CD4 T cell population is increasingly comprised of cells with a memory/activated phenotype. These effects are apparent by 2 wk postinfection, and the change is nearly complete by 6-8 wk. The phenotypic shift is paralleled by the loss of the ability of the CD4 T cells to proliferate or to produce interleukin 2 (IL-2), II.-3, IL-4, and interferon ? in response to stimulation with mitogens, superantigen, or anti-CD3. There is no obvious expansion or deletion of CD4 T cells expressing particular V/3 genes, as might be expected if a conventional superantigen were driving the changes. The results suggest, however, that the total CD4 population has been driven to anergy by some potent polyclonal stimulus directly associated with viral infection.

B Cell Immunodeficiency Fails to Develop in CD4-Deficient Mice Infected with BM5: Murine AIDS as a Multistep Disease

“…We have previously reported that following infection with BM5, the entire CD4 ϩ T cell compartment changes phenotype within 6 -8 wk, with the cells acquiring an activated/memory phenotype (L-selectin low , CD45RB low , CD69 high , and CD44 high ) (7). CD4 ϩ T cell numbers increase and there is direct evidence from in vivo bromodeoxyuridine (BrdU) incorporation studies that a large fraction of T cells divide (8).…”

“…CD4 ϩ T cell numbers increase and there is direct evidence from in vivo bromodeoxyuridine (BrdU) incorporation studies that a large fraction of T cells divide (8). However, despite this polyclonal response, the CD4 ϩ T cell compartment loses the ability to respond in vitro to polyclonal or antigenic stimuli as measured by proliferation or cytokine production (1,7).…”

“…Some B cell changes such as hypergammaglobulinemia and enhanced in vivo B cell proliferation also occur early during MAIDS. However, it is not until late in disease (around week 12) that the loss of B cell function and also the development of lymphomas become apparent (2,6,7), raising the possibility that the T cell changes precede those in the B cells and may in fact induce them.…”

“…There is growing evidence that neither specific Ag (19) nor conventional superantigens are involved in CD4 ϩ T cell activation, which occurs (7,20,21), despite earlier suggestions of superantigen involvement (14,22). We found no detectable V ␤ selectivity in vivo but rather a completely polyclonal CD4 ϩ T cell response (7,21).…”

“…There is growing evidence that neither specific Ag (19) nor conventional superantigens are involved in CD4 ϩ T cell activation, which occurs (7,20,21), despite earlier suggestions of superantigen involvement (14,22). We found no detectable V ␤ selectivity in vivo but rather a completely polyclonal CD4 ϩ T cell response (7,21). Furthermore, we showed that V ␤ 3-expressing transgenic mice were comparable to nontransgenic wild-type mice in their susceptibility to MAIDS (19), further supporting the absence of a requirement for any epitope-specific TCR recognition.…”