On the role of the inhibitory receptor LAG-3 in acute and chronic LCMV infection

Abstract

Chronic viral infections are often characterized by CD8 T-cell responses with poor cytokine secretion potential and limited expansion of the CD8 T-cell pool, collectively referred to as CD8 T-cell exhaustion. Exhaustion of lymphocytic choriomeningitis virus (LCMV)-specific CD8 T cells was shown to be partially regulated by the inhibitory receptor programmed death 1 (PD-1). Here, we demonstrate that exhausted LCMV-specific CD8 T cells also express the negative regulatory receptor lymphocyte activation gene 3 (LAG-3) which is mainly expressed on cells co-expressing the negative regulatory receptors PD-1 and Tim-3. Expression levels of LAG-3 on anti-viral CD8 T cells remain stable over short-term in vitro stimulations in presence of antigenic peptide. Nevertheless, in vitro and in vivo blockade of LAG-3 did not rescue cytokine production by virus-specific CD8 T cells and did not alter the virus titer in various organs. Likewise, chronic LCMV infection of LAG-3-/- mice led to a comparable degree of T-cell exhaustion as observed in C57BL/6 controls and to similar virus titers. Further, LAG-3 did not influence T-cell activation or cell division during chronic LCMV infection. These data suggest that even though LAG-3 is continuously up-regulated on LCMV-specific exhausted CD8 T cells, it alone does not significantly contribute to T-cell exhaustion.

Platelet production proceeds independently of the intrinsic and extrinsic apoptosis pathways

“…Blood and organs were collected 8 or 21 days after infection. Virus was propagated on L929 cells 70 .…”

Soluble T Cell Immunoglobulin Mucin Domain 3 Is Shed from CD8 + T Cells by the Sheddase ADAM10, Is Increased in Plasma during Untreated HIV Infection, and Correlates with HIV Disease Progression

“…The resulting persistent antigen levels drive a process called "T cell exhaustion," whereby responding T cells undergo hierarchical loss of their effector functions, including their ability to proliferate, their cytotoxic potential, and their ability to produce cytokines (1). Coinhibitory molecules, including programmed death receptor 1 (PD-1) (2-6), lymphocyte activation gene-3 (LAG-3) (5,7,8), carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) (9)(10)(11)(12), and T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) (4,(12)(13)(14) contribute to T cell exhaustion, reducing potentially harmful, persistent T cell activation. However, this also results in suboptimal HIV-specific responses and ultimately poor control of the virus.…”

Therapeutic Blockade of Transforming Growth Factor Beta Fails To Promote Clearance of a Persistent Viral Infection

“…CTLA-4 does not impede antiviral immunity to LCMV CL13 (3), but expression on CD4 ϩ T cells was recently shown to correlate positively with disease progression and T cell dysfunction in HIV-infected patients (30). TIM-3 and LAG-3 also appear to play a minor role in regulating antiviral immunity to LCMV CL13 (8,28,52). Neutralization of these regulators has no impact on viral clearance unless done in combination with blockade of a major regulator like PD-1.…”