The immune system constantly maintains the intricate balance necessary to eliminate pathogens while preserving tolerance to self. We have previously shown that strong immune stimulation using agonistic αCD40/IL-2 immunotherapy (IT) results in the induction of robust, antigen-nonspecific CD8-mediated antitumor responses. In addition to proinflammatory reponses, a number of suppressive pathways become activated as well following IT. We sought to determine the ability of T cells to react to various stimuli immediately following strong immune stimulation. Studies revealed that while CD8 responses remained intact, CD4+ T cells exhibited markedly diminished ability to respond to TCR engagement including lack of CD25 upregulation and proliferation. Paralysis of the naïve CD4 population resulted in the inability to respond to primary antigen in vivo. Further analysis of the naïve CD4 population revealed concomitant upregulation of SOCS3, a negative regulator of JAK/STAT signaling, including STAT5. Consistent with this, STAT5 phosphorylation was diminished in CD4+ T cells restimulated following IT further suggesting a role for SOCS3 in the paralysis. These data have significant ramifications when attempting to apply IT in cancer. It also sheds light into the immune dysfunction documented during periods of strong immune stimulation such as acute infections or sepsis.
- Copyright © 2013 by The American Association of Immunologists, Inc.