MIP-1alpha and MIP-1beta differentially mediate mucosal and systemic adaptive immunity.

Macrophage inflammatory protein-1alpha (MIP-1alpha) and MIP-1beta are distinct but highly homologous CC chemokines produced by a variety of host cells in response to various external stimuli and share affinity for CCR5. To better elucidate the role of these CC chemokines in adaptive immunity, we have characterized the affects of MIP-1alpha and MIP-1beta on cellular and humoral immune responses. MIP-1alpha stimulated strong antigen (Ag)-specific serum immunoglobulin G (IgG) and IgM responses, while MIP-1beta promoted lower IgG and IgM but higher serum IgA and IgE antibody (Ab) responses. MIP-1alpha elevated Ag-specific IgG1 and IgG2b followed by IgG2a and IgG3 subclass responses, while MIP-1beta only stimulated IgG1 and IgG2b subclasses. Correspondingly, MIP-1beta produced higher titers of Ag-specific mucosal secretory IgA Ab levels when compared with MIP-1alpha. Splenic T cells from MIP-1alpha- or MIP-1beta-treated mice displayed higher Ag-specific Th1 (interferon-gamma [IFN-gamma]) as well as selective Th2 (interleukin-5 [IL-5] and IL-6) cytokine responses than did T cells from control groups. Interestingly, mucosally derived T cells from MIP-1beta-treated mice displayed higher levels of IL-4 and IL-6 compared with MIP-1alpha-treated mice. However, MIP-1alpha effectively enhanced Ag-specific cell-mediated immune responses. In correlation with their selective effects on humoral and cellular immune responses, these chemokines also differentially attract CD4(+) versus CD8(+) T cells and modulate CD40, CD80, and CD86 expressed by B220(+) cells as well as CD28, 4-1BB, and gp39 expression by CD4(+) and CD8(+) T cells in a dose-dependent fashion. Taken together, these studies suggest that these CC chemokines differentially enhance mucosal and serum humoral as well as cellular immune responses.