T‐cell help permits memory CD8⁺ T‐cell inflation during cytomegalovirus latency

Abstract

CD4 1 T cells are implied to sustain CD8 1 T-cell responses during persistent infections. As CD4 1 T cells are often themselves antiviral effectors, they might shape CD8 1 T-cell responses via help or via controlling antigen load. We used persistent murine CMV (MCMV) infection to dissect the impact of CD4 1 T cells on virus-specific CD8 1 T cells, distinguishing between increased viral load in the absence of CD4 1 T cells and CD4 1 T-cell-mediated helper mechanisms. Absence of T-helper cells was associated with sustained lytic MCMV replication and led to a slow and gradual reduction of the size and function of the MCMV-specific CD8 1 T-cell pool. However, when virus replication was controlled in the absence of CD4 1 T cells, CD8 1 T-cell function was comparably impaired, but in addition CD8 1 T-cell inflation, a hallmark of CMV infection, was completely abolished. Thus, CD8 1 T-cell inflation during latent CMV infection is strongly dependent on CD4 1 T-cell helper functions, which can partially be compensated by ongoing lytic viral replication in the absence of CD4 1 T cells. IntroductionPersistent viral infections shape their cognate CD8 1 T cells markedly. This is most apparent in chronic infections with continuous productive viral replication such as chronic lymphocytic choriomeningitis virus (LCMV) infection in the mouse, where permanent activation of CD8 1 T cells drives these cells into exhaustion, [1][2][3][4] with the antigen load and/or duration of antigen exposure being major promoters of CD8 1 T-cell exhaustion [5].Low level of antigen persistence as seen during chronic infection with latent, reactivating viruses also shapes antigen-specific CD8 1 T-cell responses, but to a less severe extent than in situations with continuous productive viral replication. Murine CMV (MCMV) is one of the best studied examples of a chronic latent infection. Two types of virus-specific CD8 1 T-cell responses, an inflationary and a non-inflationary, can be distinguished during the course of MCMV infection [6][7][8][9]. CD8 1 T cells of the non-inflationary type resemble CD8 1 T cells that develop during acute resolved infections with respect to their kinetics, function and phenotype [7,[9][10][11][12]. In contrast, inflationary CD8 1 T cells show continued expansion after control of lytic replication, eventually stabilizing at high frequencies [6][7][8][9]. At late stages of infection, these cells are partially exhausted as they lack IL-2 secretion capacity and have reduced TNF-a production potential [7]. MCMV-specific inflationary CD8 1 T cells, in contrast to non-inflationary ones, are dependent on cognate antigen for their maintenance, are unresponsive to homeostatic cytokines [12], and exhibit an effector/effector memory phenotype. In contrast, non-inflationary CD8 1 T cells display a central memory phenotype [12,13].CD4 1 helper T cells were shown to promote priming and/or memory differentiation of CD8 1 T cells in various immunizations and acute infections [10,14]. However, whether and how CD4 1 T cells affect CD8...

Memory T cell inflation: understanding cause and effect

“…CD4 + T cells are generally important for the development of memory CD8 + T cell responses and even more so for inflationary responses [47,48]. The mechanisms for this apparently increased helper-dependence are, however, unidentified.…”

The (gradual) rise of memory inflation

“…It is important to recognize the dynamic nature of some these effects—in most model systems inflation is best studied after 50‐100 days—while priming occurs in the first week (in the case of MCMV) or up to 3 weeks (in the case of adenovirus vaccination). There are data that suggest an important role for T‐cell help in generating optimal memory populations during priming and this includes an impact on some (but not all) inflationary populations 58. Interestingly in the adenovirus model, a lack of help leads to induction of exhausted responses following vaccination 59.…”

Antiviral Therapy Can Reverse the Development of Immune Senescence in Elderly Mice with Latent Cytomegalovirus Infection

“…MCMV can infect a variety of cell types (7); however, the anatomical reservoirs of latent MCMV may be limited to sites such as the salivary glands, liver sinusoidal endothelium (8), and nonhematopoietic cells within the lymph nodes (9,10). The degree of T-cell inflation against individual viral peptides is governed by their patterns of expression and the nature of the infection model (11)(12)(13)(14).…”