Macrophages exhibit a wide variety of functions, ranging from the phagocytosis and elimination of intracellular pathogens, to homeostatic roles in maintaining organ function and development. Developing these varied, highly specialised functions is dependent on the macrophage correctly integrating cues from their extracellular environment, resulting in their differentiation into a phenotype that is uniquely tuned to the environment at hand. Three key processes in macrophage differentiation are the remodelling of morphology, the reprogramming of cellular metabolism and transcriptional remodelling to promote differential gene expression. Here, we show that the tetraspanin CD82 plays a key role in integrating these processes. Cd82-/- bone-marrow derived macrophages (BMDM) stimulated with pro-inflammatory cues (lipopolysaccharide (LPS) and interferon-gamma (IFN-γ)) had muted expression of the signature gene Nos2, concomitant with a blunted glycolytic metabolism and minimal morphological remodelling. Similarly, Cd82-/- BMDM stimulated with anti-inflammatory cues (IL-4 and IL-13) had muted expression of the signature gene Mrc1, reduced oxidative respiration and an absent elongated spindle morphology. We next infected male and female WT and Cd82-/- mice intradermally with the obligate intracellular pathogen Leishmania mexicana. Remarkably we observed a striking difference in response depending on sex. Female Cd82-/- C57BL/6 mice had persistent cutaneous lesions, associated with an increased proportion of lesion-associated Ly6Chi CD64+macrophages. By contrast, male Cd82-/- C57BL/6 mice exhibited faster resolution of cutaneous lesions. Taken together, point to a central role for CD82 in regulating macrophage differentiation to pro- and anti-inflammatory phenotypes that is critical for response to infection with L. mexicana.