αβ and γδ T‐cell networks and their roles in natural resistance to viral infections

Abstract

Both alpha beta and gamma delta T-cell populations and natural killer (NK) cells include cytotoxic, interferon (IFN)-gamma-producing lymphocytes that actively respond to viral infections. We show here that all three populations can provide "natural resistance" to viruses very early in infection and describe how the T-cell populations are modulated to provide this function. gamma delta T cells were shown to play a role in controlling vaccinia virus (VV) infections, as VV grew to much higher titers in gamma delta T-cell knockout mice than in normal mice 3-4 days post-infection. Our studies of the alpha beta T-cell responses to viruses revealed an interactive network of T cells that is modulated substantially during systemic infections. There is an induction phase associated with a massive virus-specific CD8 T-cell response, an apoptosis phase during which the T cells become sensitized to activation-induced cell death (AICD), a silencing phase, during which the T-cell number and activation state is reduced, and, finally, a memory phase associated with the very stable preservation of virus-specific memory cytotoxic T-lymphocyte precursors (pCTL). Infection of mice immune to one virus with a heterologous virus leads to a selective expansion of memory CTL cross-reacting between the two viruses, but, after homeostasis is again established, there is a quantitative reduction and qualitative alteration of memory to the first virus. Our results suggest that memory alpha beta T cells cross-reactive between heterologous viruses mediate both immunopathology and protective immunity at early stages of the second virus infection. Thus, memory alpha beta T cells can, like gamma delta T cells and NK cells, provide natural immunity to viral infections.

Selective, efficient modulation of activated CD4+ αβT cells by the novel humanized antibody GZ-αβTCR targeting human αβTCR

“…[50][51][52][53][54][55][56] Furthermore, the key role of γδT cells in primary immune responses is undisputed in CMV, HSV-1 and Candida albicans infections, pathogens that are frequent after transplantation. [57][58][59] In addition, γδT cells are crucial modulators of immune responses and decisive in the induction and maintenance of tolerance in various physiological settings [60][61][62][63] and can directly promote allograft survival. 64 GZ-αβTCR was well tolerated, congruent with the bland cytokine signature obtained in vitro when crosslinking αβT cell TCR with GZ-αβTCR.…”

Comparative assessment of virulence of recombinant vaccinia viruses expressing IL-2 and IL-15 in immunodeficient mice

“…Previous studies examining the role of IFN-␥ in mice infected with IL-2-expressing vaccinia virus in mediating the survival of these immunodeficient mice that lack functional T cells to survive an otherwise lethal infection have implicated NK cells as the primary source of induced IFN-␥ (17,27). It is important to note that extrathymically derived ␥␦-T cells present in these nude mice are also likely to be a source of IFN-␥ (29). The fact that both ␥␦-T cells and monocyte͞macrophage cells are functionally augmented by these cytokines (4) suggests that these cell populations, too, may contribute to the mitigation of virulence.…”

A Novel Serum Protein That Is Selectively Produced by Cytotoxic Lymphocytes

“…These cells also express Fas ligand (2) and/or TNF-related apoptosis-inducing ligand (TRAIL) 3 (3,4), through which they can induce apoptosis in Fas-and/or TRAIL receptors-expressing target cells (5,6). Although CTL response is primarily performed by CD8 ϩ T cells, ␥␦ T cells also elicit cytotoxic activity through similar mechanisms and play a protective role against viral and bacterial infections (7,8). CD4 ϩ T cells are generally known as Th cells that play a central role in the immune system, principally through secretion of various cytokines.…”