CD4 T Follicular Helper and Regulatory Cell Dynamics and Function in HIV Infection

Abstract

T follicular helper cells (TFH) are a specialized subset of CD4 T cells that reside in B cell follicles and promote B cell maturation into plasma cells and long-lived memory B cells. During chronic infection prior to the development of AIDS, HIV-1 (HIV) replication is largely concentrated in TFH. Paradoxically, TFH numbers are increased in early and midstages of disease, thereby promoting HIV replication and disease progression. Despite increased TFH numbers, numerous defects in humoral immunity are detected in HIV-infected individuals, including dysregulation of B cell maturation, impaired somatic hypermutation, and low quality of antibody production despite hypergammaglobulinemia. Clinically, these defects are manifested by increased vulnerability to bacterial infections and impaired vaccine responses, neither of which is fully reversed by antiretroviral therapy (ART). Deficits in TFH function, including reduced HIV-specific IL-21 production and low levels of co-stimulatory receptor expression, have been linked to these immune impairments. Impairments in TFH likely contribute as well to the ability of HIV to persist and evade humoral immunity, particularly the inability to develop broadly neutralizing antibodies. In addition to direct infection of TFH, other mechanisms that have been linked to TFH deficits in HIV infection include upregulation of PD-L1 on germinal center B cells and augmented follicular regulatory T cell responses. Challenges to development of strategies to enhance TFH function in HIV infection include lack of an established phenotype for memory TFH as well as limited understanding of the relationship between peripheral TFH and lymphoid tissue TFH. Interventions to augment TFH function in HIV-infected individuals could enhance immune reconstitution during ART and potentially augment cure strategies.

Impact of BAFF Blockade on Inflammation, Germinal Center Reaction and Effector B-Cells During Acute SIV Infection

“…BAFF neutralization failed to increase the recruitment of T FR (FoxP3 + cells in GC), thought to ameliorate selection of virus-specific B-cells and affinity maturation (79) as well as to decrease fCD8 influx. However, these fCD8 cells endowed with regulatory functions during chronic infection (80) did not change IL21 release by T FH during acute SIV infection. Similar proportions of T FH among mCD4 T-cells and average numbers of spleen T FH per GC in both groups of macaques argue for unchanged recruitment of T FH despite BAFF deprivation.…”

“…Moreover, we showed for the first time that 32% of AM and 16.5% of TLM B-cells were TACI + in Placebo macaques, respectively. Treatment by BR3-Fc decreased TACI expression in all subsets, but this decrease was significant only in RM, AM, and TLM (71,80, and 84% of decrease, respectively). Irrespective of BAFF blockade, <5% GC B-cells expressed TACI at their surface.…”

Mild profile improvement of immune biomarkers in HIV/HCV-coinfected patients who removed hepatitis C after HCV treatment: A prospective study

“…HIV infection causes a deregulation of the immune system that is not entirely reversed by suppressive cART 5 and is related to gut mucosal barrier dysfunction, inflammation, and immune activation. 43 During CHC, the immune system also plays a key role in cirrhosis progression.…”

“…1 This immunodeficiency may be reverted by suppressive combination antiretroviral therapy (cART), 2 particularly with early initiation of cART. 3 However, a large number of alterations are not completely reversed, such as deficits in CD4 + T helper cell (Th) 1, Th2, Th17, and regulatory CD4 + T cell (Treg) responses, [4][5][6][7][8][9] persistent immune activation, 7 systemic inflammation, 3 gut mucosal barrier dysfunction and dysbiosis; [10][11][12] which may increase the risk for of both AIDS and non-AIDS-related conditions and death. 13 , 14 Hepatitis C virus (HCV) infection is common among HIVinfected subjects, who develop chronic hepatitis C (CHC) over decades.…”

CD4+ T Cell Differentiation in Chronic Viral Infections: The Tfh Perspective

“…Moreover, there are major efforts underway to develop putative prophylactic and therapeutic antibody-based vaccines for HIV-1 infection, and these may heavily depend on effective Tfh responses 117 , because production of effective antibodies by vaccination requires functional Tfh:B cell interactions. Tfh cells are therefore an important component of adaptive immunity, and a deeper understanding of the perturbed functional role of these cells from HIV infection may improve our understanding of HIV pathogenesis, prevention, and presumably, future cure of HIV infections 118 . Nevertheless, interrogation of Tfh in lymph nodes and other lymphoid tissues, as well as the location where Tfh:B cell interactions occur, is necessarily limited by access to tissues, although tissue-based research remains a vital goal.…”