[Show abstract][Hide abstract] ABSTRACT: The dissemination of HIV from an initial site of infection is facilitated by motile HIV-infected CD4(+) T-cells. However, the impact of infected target cell migration on antigen recognition by HIV-specific CD8(+) T-cells is unclear. Using a 3D in vitro model of tissue, we visualized dynamic interactions between HIV-infected or peptide-pulsed CD4(+) T-cells and HIV-specific CD8(+) T-cells. CTLs engaged motile HIV-infected targets, but ∼50% of targets broke contact and escaped. In contrast, immobilized target cells were readily killed, indicating target motility directly inhibits CD8(+) T-cell function. Strong calcium signals occurred in CTLs killing a motile target but calcium signaling was weak or absent in CTLs which permitted target escape. Neutralization of adhesion receptors LFA-1 and CD58 inhibited CD8(+) T-cell function within the 3D matrix, demonstrating that efficient motile target lysis as dependent on adhesive engagement of targets. Antigen sensitivity (a convolution of antigen density, TCR avidity and CD8 coreceptor binding) is also critical for target recognition. We modulated this parameter (known as functional avidity but referred to here as "avidity" for the sake of simplicity) by exploiting common HIV escape mutations and measured their impact on CTL function at the single-cell level. Targets pulsed with low avidity mutant antigens frequently escaped while CTLs killed targets bearing high avidity antigen with near-perfect efficiency. CTLs engaged, arrested, and killed an initial target bearing high avidity antigen within minutes, but serial killing was surprisingly rare. CD8 cells remained committed to their initial dead target for hours, accumulating TCR signals that sustained secretion of soluble antiviral factors. These data indicate that high-avidity CD8(+) T-cells execute an antiviral program in the precise location where antigen has been sensed: CTL effector functions are spatiotemporally coordinated with an early lytic phase followed by a sustained stationary secretory phase to control local viral infection.
[Show abstract][Hide abstract] ABSTRACT: Under persistent antigenic stimulation, virus-specific CD8⁺ T cells become increasingly dysfunctional and up-regulate several inhibitory molecules such as killer lectin-like receptor G1 (KLRG1). Here, we demonstrate that HIV-1 antigen-specific T cells from subjects with chronic-progressive HIV-1 infection have significantly elevated KLRG1 expression (P < .001); show abnormal distribution of E-cadherin, the natural ligand of KLRG1, in the intestinal mucosa; and have elevated levels of systemic soluble E-cadherin (sE-cadherin) that significantly correlate with HIV-1 viral load (R = 0.7, P = .004). We furthermore demonstrate that in the presence of sE-cadherin, KLRG1(hi) HIV-1-specific CD8⁺ T cells are impaired in their ability to respond by cytokine secretion on antigenic stimulation (P = .002) and to inhibit viral replication (P = .03) in vitro. Thus, these data suggest a critical mechanism by which the disruption of the intestinal epithelium associated with HIV-1 leads to increased systemic levels of sE-cadherin, which inhibits the effector functions of KLRG1(hi)-expressing HIV-1-specific CD8⁺ T cells systemically.
[Show abstract][Hide abstract] ABSTRACT: Functional defects in cytotoxic CD8+ T cell responses arise in chronic human viral infections, but the mechanisms involved are not well understood. In mice, CD4
cell-mediated interleukin-21 (IL-21) production is necessary for the maintenance of CD8+ T cell function and control of persistent viral infections. To investigate the potential role of IL-21 in a chronic human
viral infection, we studied the rare subset of HIV-1 controllers, who are able to spontaneously control HIV-1 replication
without treatment. HIV-specific triggering of IL-21 by CD4+ T cells was significantly enriched in these persons (P = 0.0007), while isolated loss of IL-21-secreting CD4+ T cells was characteristic for subjects with persistent viremia and progressive disease. IL-21 responses were mediated by
recognition of discrete epitopes largely in the Gag protein, and expansion of IL-21+ CD4+ T cells in acute infection resulted in lower viral set points (P = 0.002). Moreover, IL-21 production by CD4+ T cells of HIV controllers enhanced perforin production by HIV-1-specific CD8+ T cells from chronic progressors even in late stages of disease, and HIV-1-specific effector CD8+ T cells showed an enhanced ability to efficiently inhibit viral replication in vitro after IL-21 binding. These data suggest that HIV-1-specific IL-21+ CD4+ T cell responses might contribute to the control of viral replication in humans and are likely to be of great importance
for vaccine design.
Full-text · Article · Nov 2010 · Journal of Virology