Preservation of T-Helper Type 17 Cells in Idiopathic CD4+Lymphopenia: A New Perspective Relevant to HIV Infection?

CD4 lymphopenia is a common hallmark of both idiopathic CD4 lymphopenia (ICL) and human immunodeficiency virus (HIV) infection, leading to opportunistic infections. In HIV infection, a profound CD4 T-cell depletion occurs in the gut very early in primary infection to a greater extent than in blood [1]. This depletion occurs both in humans and in nonhuman primate models, with a predominant depletion of memory CCR5 CD4 T cells [2] and of the T-helper type 17 (Th17) subset among CD4 T cells [3]. Chronic immune activation is another hallmark of HIV infection, and the levels of activated T lymphocytes correlate with the progression of the disease in untreated HIV type 1 (HIV)–infected patients [4]. In 2006, Brenchley et al reported that microbial translocation was abnormally high during HIV infection and that the level of lipopolysaccharide (LPS), a component of the wall of gram-negative rods, in blood was positively correlated with the immune activation of T cells [5]. This suggested that alterations of intestinal epithelium integrity contribute to the chronic activation state present in HIVinfected individuals. Antiretroviral therapy (ART) is not able to completely normalize the levels of immune activation and the CD4 T-cell counts in patients with chronic HIV infection [6]. Developing new therapeutic strategies to supplement ART and allow so-called efficient CD4 T-cell restoration is, therefore, an important goal. However, what defines efficient CD4 T-cell restoration remains unclear. Does it rely on absolute numbers or T-cell subset distribution? Is T-cell lymphopenia deleterious predominantly in mucosal sites or in peripheral blood? The study reported by Kovacs et al [7] in this issue of The Journal of Infectious Diseases provides interesting insights in the context of ICL. ICL is a rare syndrome characterized by CD4 T-cell lymphopenia and opportunistic infections in the absence of HIV infection or any other known immunodeficiency or therapy associated with lymphopenia. Interestingly, ICL recapitulates several features of HIV infection, such as increased CD4 T-cell activation, lower proportion of naive CD4 T cells, impaired T-cell receptor signaling, decreased interleukin 7 and interleukin 12 responsiveness, and accelerated T-cell senescence [8–11]. A defect in chemokine receptor expression [12] was also described in ICL, suggesting decreased chemotactic responses and disruption of CD4 homing. Indeed, discrepancies in lymphopenia between lymphoid organs and/or effector sites such as the gut have been described. In mouse models of aging, peripheral CD4 lymphopenia is associated with a significant decrease of CD4 T cells in lymphoid organs, contrasting with the preservation and accumulation of CD4 T cells in the gut [13]. Peripheral blood lymphopenia could be the result of a redistribution of CD4 T cells, rather than generalized CD4 T-cell decay. In this report, Kovacs et al [7] described the extent of CD4 T-cell lymphopenia developing in the colonic mucosa of patients with ICL. Focusing on the gut mucosa is, indeed, a crucial point since gut-associated mucosa has been considered a major site of CD4 T-cell accumulation. The authors provide evidence of T-cell depletion in the colonic mucosa of the patients with this rare syndrome. Their results are supported by a large number of patients studied, despite the rarity of the syndrome. Compared with healthy controls, they found depletion of CD4 and CD8 T cells in patients with ICL. This decrease of T cells in the gut did not seem to be related to a homing defect, as the expression of the integrin β7 was not different, compared with healthy controls. However, the proportions of T-cell Received and accepted 11 May 2015; electronically published 20 May 2015. Correspondence: Olivier Lambotte, MD, PhD, CHU Bicêtre, Service de Médecine Interne et Immunologie Clinique, 78 rue du Général Leclerc, 94275, le Kremlin Bicêtre, France (olivier.lambotte@bct.aphp.fr). The Journal of Infectious Diseases 2015;212:1531–3 © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/infdis/jiv285