CD4⁺CD25⁺T Regulatory Cells Inhibit CD8⁺IFN-γ Production During Acute and Chronic FIV Infection Utilizing a Membrane TGF-β-Dependent Mechanism

Abstract

CD8þ lymphocytes are critical to the control and elimination of viral pathogens. Impaired CD8 þ responses are well recognized in lentiviral infections; however, the mechanisms underlying CD8 þ impairment remain elusive. Using the feline immunodeficiency virus (FIV) model for human AIDS, we reported previously that CD4 þ CD25 þ Treg cells in both the acute and long-term, asymptomatic phase of infection are constitutively activated and suppress CD4 þ CD25-T cell responses. In the current study, we have demonstrated that CD4 þ CD25 þ Treg cells suppress CD8 þ responses to immune stimulation during both the acute and chronic, asymptomatic phase of FIV infection and that the mechanism of suppression may be mediated by membrane-þ lymphocytes from lymph node suspensions significantly enhanced production of IFN-g during the acute phase of infection and coculture of CD8 þ lymphocytes with CD4 þ CD25 þ lymphocytes resulted in suppression of CD8 þ IFN-g during both the acute and chronic stages of infection. FACS analysis indicated that there was TGF-bRII upregulation on CD8 CD25þ subset in chronically infected cats. In support of activation of the TGF-b signaling pathway, Western blotting showed Smad 2 phosphorylation in CD8coculture. These results demonstrate the suppressive effect CD4 þ CD25 þ Treg cells have on the CD8 þ immune response during the acute and chronic stages of FIV infection and suggest that the mechanism of suppression may be mediated by mTGF-b.

Feline Glycoprotein A Repetitions Predominant Anchors Transforming Growth Factor Beta on the Surface of Activated CD4+CD25+Regulatory T Cells and Mediates AIDS Lentivirus-Induced T Cell Immunodeficiency

“…1,2 Treg cells also shape the pathogenesis of viral infections by controlling inflammation from excessive activation of T and B effector subsets. [3][4][5][6][7] The study of Treg population dynamics and function has thus become important for an array of diseases. However, their purification has been problematic as there has been no marker unique to Treg cells.…”

“…10,14 While numerous mechanisms for Treg cell-mediated suppression have been proposed, studies on murine, human, and feline Treg cells have identified TGFb signaling to be important. 5,[15][16][17][18] In the case of autoimmune disease, it has been reported that membrane bound TGFb (mTGFb) mediates T cell suppression by ligation of the TGFb receptor (TGFbRII) expressed on the surface of activated target Th cells. [16][17][18][19] We have demonstrated that engagement of the TGFbRII on target cells activates the SMAD pathway, 5 which may in turn induce the expression of Foxp3, a transcription repressor of IL-2.…”

Infection with Feline Immunodeficiency Virus Directly Activates CD4 + CD25 + T Regulatory Cells

“…Studies have reported that TGF-␤ is expressed on the surface of activated Treg cells and plays a role in contact-dependent Tregmediated suppression (3,15,17,18). Furthermore, we have demonstrated that GARP forms a complex with membrane-bound TGF-␤ (mTGF-␤) on activated Treg cells (18).…”

“…ϩ regulatory T cells (Treg cells), currently defined by constitutive expression of the high-affinity interleukin-2 (IL-2) receptor CD25 and the transcription factor Foxp3, play an important role in controlling autoimmune disease and shaping the pathogenesis of viral infections by regulating expansion of T and B effector subsets (1)(2)(3)(4)(5)(6)(7). Although Treg cells play an important role in preventing excessive inflammation associated with immune responses to infection, they may in the process prematurely abort protective T and B cell immune responses and allow chronic viremia and more severe pathogenesis.…”

Immune recovery after fluid resuscitation in rats with severe hemorrhagic shock

“…A sufficient quantity of Tregs is critical in keeping inflammation balance and reducing tissue injury (Li et al, 2009;Fogle et al, 2010b;Tang et al, 2014;Zhao et al, 2015;Zhang et al, 2016). Excessive activity or quantity of Tregs can promote infectious deterioration, sepsis, or tumor immune escape, whereas an insufficient amount can result in overactive inflammatory responses (Burgents et al, 2010;Fogle et al, 2010a;Carambia et al, 2014). Tregs have been shown to be differentially influenced by various resuscitation fluids after hemorrhagic shock (Murao et al, 2009;Isayama et al, 2012).…”