The effects of TLR agonists on the clonal expansion of CD4+ T cells

The initial burst size of a T cell response in vivo is often indicative of the effectiveness of an immune response to infection. It is therefore important to understand how immunological adjuvants, which are needed for effective immunity, contribute to increases in burst size following T cell activation. Recent advances in immunological research have shown that compounds with adjuvant activity are frequently agonists of the "Toll-like" family of receptors (TLRs). The TLRs are now considered to be the means by which the innate immune system senses microbial infection and signals the adaptive immune response to proceed. Effects of TLR signaling on the adaptive T cell response were studied here by treating experimental mice with antigenic peptides in the presence or absence of TLR agonists. Abortive clonal expansion in the absence of TLR agonist stimulation was marked by efficient cell division without a concomitant increase in burst size. The addition of various TLR agonists caused a small increase in the cellular proliferation of activated CD4+ T cells, but allowed newly generated daughter cells to accumulate much more efficiently throughout clonal expansion. Furthermore, by analyzing the differences in cellular division and burst size, only about 15--25% of the TLR-dependent increase in a clonal population of T cells was found to be attributable to increased cellular division. The balance of this increase in activated T cells was due to increased cell survival during clonal expansion, indicating that rates of cell loss during proliferation in vivo are high unless TLR agonists are present.; These initial observations were made with highly inflammatory compounds such as the bacterial lipopolysaccharide (LPS). Although LPS exerts strong immunostimulatory effects, its extreme toxicity precludes its use in clinical settings. This pattern has contributed to the view that immunological adjuvants need to be highly inflammatory to be maximally effective in enhancing T cell effects. The effects of the TLR4 agonists LPS and its less toxic derivatives, monophosphoryl lipid A (MPL) and a chemical mimetic called RC529 were compared to determine if inflammatory signaling was required to enhance CD4 + T cell clonal expansion, long term survival and T helper 1 (Th1) differentiation. LPS, MPL, and RC529 had similar effects on CD4+ T cell clonal expansion, cell division and ex vivo survival. Analysis of the ability of activated CD4+ T cells to produce IFN-gamma following a 21 day immunization and challenge protocol with LPS and MPL resulted in similar Th1 differentiation, however, LPS was more effective in promoting long term CD4+ T cell survival, because nearly 6 fold more cells were recovered following immunization/challenge as compared to treatment with MPL. These results indicate that low-inflammation adjuvants, such as MPL and RC529, are capable of enhancing short term CD4+ T cell clonal expansion and Th1 differentiation, but inflammatory signaling aids in the long term survival of activated T cells.