CD4+ T cells become ineffective if repeatedly stimulated through their T cell receptors (TCRs), according to a study by Jelley-Gibbs and colleagues on page 1101. The functional demise of these cells may help explain why persisting pathogens, such as Mycobacterium tuberculosis and HIV, are associated with ineffective CD4+ T cell responses during the chronic phase of infection.

CD4+ T cells that undergo multiple rounds of stimulation (Th1RS) are unable to protect mice against influenza infection.

Chronic infections have been shown to induce exhaustion or functional unresponsiveness in cytotoxic CD8+ T cells, but their effect on CD4+ T helper cells has not been well studied. Jelley-Gibbs et al. now show that repeated stimulation of CD4+ T cells generated effector cells that were more activated, based on the expression of activation markers CD69 and CD62L, than cells stimulated only once but that secreted lower levels of the cytokines interferon-γ (IFN-γ) and interleukin-4 (IL-4). These repeatedly stimulated cells could not provide help to antibody-producing B cells, nor could they protect against influenza virus infection when transferred into mice.

The decreased function of these repeatedly stimulated cells could not be explained by the down-regulation of their TCRs, whose levels were only marginally affected by the multiple rounds of stimulation. The authors are now studying chromatin remodeling at the IFNγ and IL-4 loci for possible clues to the decreased cytokine production.