HIV-Infected Spleens Present Altered Follicular Helper T Cell (Tfh) Subsets and Skewed B Cell Maturation

Abstract

Follicular helper T (Tfh) cells within secondary lymphoid organs control multiple steps of B cell maturation and antibody (Ab) production. HIV-1 infection is associated with an altered B cell differentiation and Tfh isolated from lymph nodes of HIV-infected (HIV+) individuals provide inadequate B cell help in vitro. However, the mechanisms underlying this impairment of Tfh function are not fully defined. Using a unique collection of splenocytes, we compared the frequency, phenotype and transcriptome of Tfh subsets in spleens from HIV negative (HIV-) and HIV+ subjects. We observed an increase of CXCR5+PD-1highCD57-Tfh and germinal center (GC) CD57+ Tfh in HIV+ spleens. Both subsets showed a reduced mRNA expression of the transcription factor STAT-3, co-stimulatory, regulatory and signal transduction molecules as compared to HIV- spleens. Similarly, Foxp3 expressing follicular regulatory T (Tfr) cells were increased, suggesting sustained GC reactions in chronically HIV+ spleens. As a consequence, GC B cell populations were expanded, however, complete maturation into memory B cells was reduced in HIV+ spleens where we evidenced a compromised production of B cell-activating cytokines such as IL-4 and IL-10. Collectively our data indicate that, although Tfh proliferation and GC reactions seem to be ongoing in HIV-infected spleens, Tfh “differentiation” and expression of costimulatory molecules is skewed with a profound effect on B cell maturation.

Impact of Chronic HIV/SIV Infection on T Follicular Helper Cell Subsets and Germinal Center Homeostasis

“…In the context of HIV/SIV infection, several groups reported higher plasma levels of IL-6 (13, 21). However, we and others (22) did not find any difference in the amount of secreted IL-6 between HIV-infected and -uninfected spleens upon activation (8). Once engaged into Tfh differentiation, the sequential differentiation model proposes that pTfh/B cell interactions dictate the fate of Tfh cells.…”

“…LN-resident helper T cells (Tfh and non-Tfh) showed replicative virus, while clonally expanded blood CD4 T cells harbor inducible provirus (11). However, despite their high susceptibility to HIV/SIV infection, many studies reported an accumulation of tissue-resident or cTfh populations during the chronic phases of infection (7, 8, 12, 13). In addition, Hong et al demonstrate that after a rapid expansion of GCs during the acute phase, slowly proliferative Tfh cells accumulate during the chronic phase of SIV infection (14).…”

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

“…The relationship between HIV and Tfh is further complicated by the fact that Tfh are a major cellular reservoir of replication-competent virus 51,111–114 . As a result, HIV-1 has been associated with increased frequencies of the very cell type it infects 51,111 .…”

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…The frequency of Tfr cells within total LN CD4 + T cells does not appear to be increased during chronic SIV282, 283 or HIV‐1 infection,284 although the absolute number of Tfr cells is increased. One report suggests that the Tfr cell frequency in the spleen may be increased during HIV‐1 infection, however 285. Two studies in which the LN Tfr:Tfh cell ratio was analyzed in macaques chronically infected with SIV report conflicting results, with one finding an increase284 and the other a decrease 283.…”