CD4 T cells are typically portrayed as playing a supportive role in the generation and maintenance of immune responses, as their alternative name – helper cells – suggests. But over the past decade, studies have shown that there are a number of settings in which antigen-specific CD4 T cells exert direct cytotoxic activity (a capacity that was once believed to be an artifact of prolonged in vitro culture).
Two new papers describe the presence of cytotoxic virus-specific CD4 T cells in SIV and HIV infection, respectively. The first study, led by Jonah Sacha, obtained Gag- and Nef-specific CD4 T cells from a group of elite controller macaques infected with SIVmac239. The researchers had noticed that, after an experiment in which CD8 T cells were depleted, the animals experienced a rebound in viral load that was subsequently brought back down to undetectable levels. This regaining of control over viral replication was associated with an expansion of their Gag- and Nef-specific CD4 T cell responses, an observation that prompted the current study.
In Sacha’s in vitro analyses, cytotoxic Gag- and Nef-specific CD4 T cells were unable to recognize SIV-infected CD4 T cells, but efficiently recognized and killed infected macrophages. Recognition occurred very rapidly, within 1-2 hours, with activity peaking between 6 and 24 hours. The cytotoxic CD4 T cells consistently eliminated 30-40% of SIV-infected macrophages in culture. Sacha and colleagues conclude by stating “on the basis of the data presented here, we speculate that Gag- and Nef-specific CD4 T cells may play a more important role in the antiretroviral immune response than previously appreciated.”
The second paper, by Nan Zheng and colleagues from Kumamoto University, identifies cytotoxic Nef-specific CD4 T cells in 4/9 individuals analyzed. In this study, the Nef-specific CD4 T cells are reported to kill both HIV-infected macrophages and CD4 T cells, but the activity against macrophages is shown to be superior.
Taken together, the findings suggest that it might be worth investigating whether cytotoxic virus-specific CD4 T cells can be induced by vaccination. Perhaps of note, one previous report from Ron Desrosiers laboratory has suggested that effector CD4 T cells with a cytotoxic phenotype (expressing perforin and the degranulation marker CD107) contribute to the protection obtained with live-attenuated SIV vaccines.
The PNAS paper is Open Access, click the title link for the full PDF.
PNAS Published online before print May 28, 2009, doi: 10.1073/pnas.0813106106
Jonah B. Sacha a,1,2, Juan P. Giraldo-Vela a,1, Matthew B. Buechler a, Mauricio A. Martins a, Nicholas J. Maness a, Chungwon Chung a, Lyle T. Wallace a, Enrique J. León a, Thomas C. Friedrich b, Nancy A. Wilson a, Atsunobu Hiraoka and David I. Watkins a
a Departments of aPathology and Laboratory Medicine andb Pathobiological Sciences, University of Wisconsin, Madison, WI 53715; and c Osaka Dental University, Osaka 540-0008, Japan
1J.B.S. and J.P.G.-V. contributed equally to this work.
The precise immunological role played by CD4+ T cells in retroviral infections is poorly defined. Here, we describe a new function of these cells, the elimination of retrovirus-infected macrophages. After experimental CD8+ cell depletion, elite controlling macaques with set-point viral loads ≤500 viral RNA copies/mL mounted robust Gag- and Nef-specific CD4+ T cell responses during reestablishment of control with ≥54% of all virus-specific CD4+ T cells targeting these 2 proteins. Ex vivo, these simian immunodeficiency virus (SIV)-specific CD4+ T cells neither recognized nor suppressed viral replication in SIV-infected CD4+ T cells. In contrast, they recognized SIV-infected macrophages as early as 2 h postinfection because of presentation of epitopes derived from virion-associated Gag and Nef proteins. Furthermore, virus-specific CD4+ T cells displayed direct effector function and eliminated SIV-infected macrophages. These results suggest that retrovirus-specific CD4+ T cells may contribute directly to elite control by inhibiting viral replication in macrophages.
JVI Accepts, published online ahead of print on 20 May 2009
J. Virol. doi:10.1128/JVI.00513-09
Nan Zheng, Mamoru Fujiwara, Takamasa Ueno, Shinichi Oka, and Masafumi Takiguchi
Division of Viral Immunology and Division of Infectious Disease, Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811; and AIDS Clinical Center, International Medical Center of Japan, 1-21-1, Toyama, Shinjuku, Tokyo 162-8655, Japan
A restricted number of studies have shown that HIV-1-specific cytotoxic CD4+ T cells are present in HIV-1-infected individuals. However, the roles of this type of CD4+ T cell in the immune responses against an HIV-1 infection remain unclear. In this study, we identified novel Nef epitope-specific HLA-DRB1*0803-restricted cytotoxic CD4+ T cells. The CD4+ T cell clones specific for Nef187-203 showed strong IFN-production after having been stimulated with autologous B-LCLs infected with Nef recombinant vaccinia virus or pulsed with heat-inactivated virus particles, indicating the presentation of the epitope antigen through both exogenous and endogenous MHC class II processing pathways. Nef187-203-specific CD4+ T cell clones exhibited strong cytotoxic activity against both HIV-1-infected macrophages and CD4+ T cells from an HLA-DRB1*0803+ donor. In addition, these Nef-specific cytotoxic CD4+ T cell clones exhibited strong ability to suppress HIV-1 replication in both macrophages and in CD4+ T cells in vitro. Nef187-203-specific cytotoxic CD4+ T cells were detected in cultures of peptide-stimulated PBMC and in ex vivo PBMC from 40% and 20% of DRB1*0803+ donors, respectively. These results suggest that HIV-1-specific CD4+ T cells may directly control HIV-1-infection in vivo by suppressing virus replication in HIV-1 natural host cells.