FOXP3+Helios+ Regulatory T Cells, Immune Activation, and Advancing Disease in HIV-Infected Children

Abstract

Regulatory T cells (Tregs) are functionally suppressive CD4 T cells, critical for establishing peripheral tolerance and controlling inflammatory responses. Previous reports of Tregs during chronic HIV disease have conflicting results with higher or lower levels compared to controls. Identifying true Tregs with suppressive activity proves challenging during HIV infection, as traditional Treg markers, CD25 and FOXP3, may transiently up-regulate expression as a result of immune activation. Helios is an Ikaros family transcription factor that marks natural Tregs with suppressive activity and does not up-regulate expression after activation. Coexpression of FOXP3 and Helios has been suggested as a highly specific marker of “bona fide” Tregs. We evaluated Treg subsets by FOXP3 co-expressed with either CD25 or Helios and their association with HIV disease progression in perinatally-infected HIV positive children. Identifying Tregs by FOXP3 coexpression with Helios rather than CD25 revealed markedly higher Treg frequencies, particularly in HIV+ children. Regardless of ART, HIV infected children had a selective expansion of memory FOXP3+Helios+ Tregs. The rise in memory Tregs correlated with declining HIV clinical status, indicated by falling CD4 percentages and CD4:CD8 ratios and increasing HIV plasma viremia and immune activation. In addition, untreated HIV+ children exhibited an imbalance between the levels of Tregs and activated T cells. Finally, memory Tregs expressed immune activation markers CD38 and Ki67 and exhaustion marker, PD-1, that tightly correlated with a similar phenotype in memory CD4 T cells. Overall, HIV infected children had significant disruptions of memory Tregs that associated with advancing HIV disease.

Highly-Exposed HIV-1 seronegative Female Commercial Sex Workers sustain in their genital mucosa increased frequencies of tolerogenic myeloid and regulatory T-cells

“…This is also in agreement with previous findings showing elevated frequencies of Tregs in the blood of HESN CSWs from Kenya46. The higher expression levels of PD-1 we report for endocervical Tregs and Tr1 of HESNs could reflect T-cell exhaustion, however we prefer the view by which these cells are in an homeostatic activated status, possibly regulating cytotoxic T lymphocyte (CTL) or DC activities via PD-1L4748, which likely confers an advantage to these individuals. Furthermore, endocervical Tregs and Tr1 cells from HESN also expressed higher levels of IL-10 and CTLA-4, respectively, which again reflect their regulatory activity47.…”

B Cell Requirement for Robust Regulatory T Cell Responses to Friend Retrovirus Infection

“…In HIV infections, Tregs play complex roles, postulated to be both beneficial in downregulating immune hyperactivation and detrimental in suppressing antiviral immune-mediated virus clearance ( 67 , 68 ). A recent study using FOXP3 and Helios to label Tregs indicated that HIV-1-infected children had expanded FOXP3 + Helios + subsets and that increased Treg levels were associated with advanced disease ( 69 ). Of course, it is still completely unknown whether B cells play any role in Treg expansion during HIV infections or even whether it would be beneficial to patients to modulate Treg responses either up or down.…”

TIGIT and Helios Are Highly Expressed on CD4+ T Cells in Sézary Syndrome Patients

“…Helios is a transcription factor in the Ikaros family present in regulatory T cells. Like TIGIT, Helios has inhibitory activity and plays a role in anti-tumor immunity (Khaitan et al , 2016; Muto et al , 2015; Sebastian et al , 2016). The expression and role of Helios and TIGIT in SS has not been explored, but given the immunosuppressive nature of the disease, both molecules may potentially contribute to this process.…”