A Natural Immunological Adjuvant Enhances T Cell Clonal Expansion through a CD28-dependent, Interleukin (IL)-2–independent Mechanism

Abstract

The adoptive transfer of naive CD4+ T cell receptor (TCR) transgenic T cells was used to investigate the mechanisms by which the adjuvant lipopolysaccharide (LPS) enhance T cell clonal expansion in vivo. Subcutaneous administration of soluble antigen (Ag) resulted in rapid and transient accumulation of the Ag-specific T cells in the draining lymph nodes (LNs), which was preceded by the production of interleukin (IL)-2. CD28-deficient, Ag-specific T cells produced only small amounts of IL-2 in response to soluble Ag and did not accumulate in the LN to the same extent as wild-type T cells. Injection of Ag and LPS, a natural immunological adjuvant, enhanced IL-2 production and LN accumulation of wild-type, Ag-specific T cells but had no significant effect on CD28-deficient, Ag-specific T cells. Therefore, CD28 is critical for Ag-driven IL-2 production and T cell proliferation in vivo, and is essential for the LPS-mediated enhancement of these events. However, enhancement of IL-2 production could not explain the LPS-dependent increase of T cell accumulation because IL-2–deficient, Ag-specific T cells accumulated to a greater extent in the LN than wild-type T cells in response to Ag plus LPS. These results indicate that adjuvants improve T cell proliferation in vivo via a CD28-dependent signal that can operate in the absence of IL-2.

Soluble Antigen and CD40 Triggering Are Sufficient to Induce Primary and Memory Cytotoxic T Cells

“…Induction of anergy rather than deletion may also occur in the absence of CD40 ligation, although in the system described in this work, this was not observed. The necessity for inflammatory signals, such as CD40 activation, to drive productive CD4 and Ab responses has been previously demonstrated (47)(48)(49). In the case of those CD8 T cell responses that require CD4 T cell help, it is known that CD40-mediated activation of APC or virus infection of APC can bypass the CD4 T cell requirement (11)(12)(13).…”

Peptide-stimulated DO11.10 T cells divide well but accumulate poorly in the absence of TLR agonist treatment

“…One possibility is that clonal deletion of potentially autoreactive T cells is easier to achieve under conditions of partial mobilization, when the activated cells might be especially sensitive to removal. However, 'adjuvant-free' stimulation typically does not lead to a complete loss of DO11.10 T cells from peripheral tissues, and the residual cells often show T regulatory activity upon re-exposure to the originally stimulating antigen [5,36]. It is possible that abortive stimulation serves to achieve limited clonal expansion and differentiation to a phenotype that can reinforce tolerance to a given antigen, rather than simply failing to respond in the first place.…”

“…This argument has been supported primarily by experiments in which adjuvants, such as the TLR4 agonist lipopolysaccharide (LPS), cause a moderate increase in the peak burst size of superantigen-responsive T cells, while protecting activated T cells from growth factor withdrawal during the ensuing clonal contraction [7,11]. In contrast, peptidebased models of adjuvant effects show tremendous increases in burst size followed by relatively steep clonal contraction [12]. The differences in these models raise the possibility that adjuvant effects on T cell responses to 'normal' antigens are more the result of adjuvantinduced cellular division than of adjuvant-dependent post-peak survival.…”

New TCR Transgenic Model for Tracking Allospecific CD4 T-Cell Activation and Tolerance in Vivo

“…Previous studies have demonstrated that CD28 costimulation is required for initiating and sustaining T-cell clonal expansion and differentiation in response to antigen recognition (21)(22)(23)(24)(25). Furthermore, CD28-B7 costimulatory blockade has been shown to inhibit clonal expansion (26) and effector cell differentiation in vivo (27).…”