Roles of CD4+ T-cell-independent and -dependent antibody responses in the control of influenza virus infection: evidence for noncognate CD4+ T-cell activities that enhance the therapeutic activity of antiviral antibodies.

Previous studies have indicated that B cells make a significant contribution to the resolution of influenza virus infection. To determine how B cells participate in the control of the infection, we transferred intact, major histocompatibility complex class II (MHC-II)-negative or B-cell receptor (BCR)-transgenic spleen cells into B-cell-deficient and CD8(+) T-cell-depleted muMT mice, termed muMT(-8), and tested them for ability to recover from infection. muMT(-8) mice that received no spleen cells invariably succumbed to the infection within 20 days, indicating that CD4(+) T-cell activities had no significant therapeutic activity on their own; in fact, they were harmful and decreased survival time.

The simian immunodeficiency virus envelope glycoprotein contains two epitopes presented by the Mamu-A*01 class I molecule.

Cytotoxic T lymphocyte (CTL) responses against the simian immunodeficiency virus (SIV) envelope and Gag proteins were monitored in a Mamu-A*01-positive rhesus macaque infected with SIVsmE660. Peripheral blood mononuclear cells (PBMC) cultured with synthetic peptides spanning the entire gp160 and Gag coding region recognized a total of three epitopes. One located in Gag was identified as the previously described Mamu-A*01-restricted p11cC-->M epitope (CTPYDINQM).

Treatment of influenza virus-infected SCID mice with nonneutralizing antibodies specific for the transmembrane proteins matrix 2 and neuraminidase reduces the pulmonary virus titer but fails to clear the infection.

Antibodies (Abs) can contribute to the cure of a viral infection, in principle, in two ways by: (1) binding to infected cells and thereby reducing the production of progeny virus [here termed cell-targeting (CT) activity] and (2) reacting with released progeny virus and thereby inhibiting the spread of the infection [termed virus neutralizing (VN) activity]. We have previously shown that a pulmonary influenza virus infection in severe combined immunodeficient mice could be cured by treatment of these mice with hemagglutinin (HA)-specific monoclonal Abs (mAbs) that mediated both of the above activities. Although the therapeutic activity of these mAbs correlated with their VN activity, it remained unclear how much their CT activity contributed to the Ab-mediated recovery process.

CD4+ T cells are ineffective in clearing a pulmonary infection with influenza type A virus in the absence of B cells.

Recovery from influenza virus infection is dependent on T cell functions which can be provided either by CD8 or CD4 T cells. To identity the functions involved in recovery promoted by CD4 T cells, we have studied the course of the infection in B-cell deficient micro MT mice which had been depleted of CD8 T cells by antibody treatment. Upon infection with PR8 [A/PR/8/34(H1N1)], such B- and CD8 T cell-deficient mice mounted strong CD4 T cell responses that were comparable in size and cytokine secretion to those seen in intact mice.

Role of the B-cell response in recovery of mice from primary influenza virus infection.

Recovery from influenza virus infection has long been known to require an intact T-cell compartment. More recent studies revealed that CD8 and CD4 T cells can promote recovery through independent mechanisms. The CD4 T-cell-dependent recovery process appears to operate primarily through promotion of the T-dependent antibody response as B-cell-deficient microMT mice cannot recover from infection if they have been depleted of CD8 T cells.